US stock - ACTC.OB, now changed to OCAT (Ocata Therapeutics)

IpohMan69

Another milestone reached!!! I am getting excited.

http://finance.yahoo.com/news/ac ... tter-123000950.html

IpohMan69

For those of you interested in this, here is a youtube audio(video is really static with a picture) uploaded and also transcripts in the middle of this thread courtesy of a lady good at it as she is a professional on transcribing.

The video is provided by an iCell member went to the conference hosted by the FFB ( Foundation for Fighting Blindness) in January. Dr. Dean Eliott is one of the doctor doing the clinical trial for ACT.

http://investorstemcell.com/foru ... ses-media/30383.htm

IpohMan69

I listened to the quarterly conference call today for first quarter of 2013. Here is the link where the replay can be listen for two weeks from today.

https://us.reg.meeting-stream.co ... a399de00996fc843a28

Courtesy of again, iCell member for the transcript of the call in below. A lot of good information and we are still on track nicely.

ACTC Conference call 5/09/13:

Gary: Thanks Kathy. I would like to take this opportunity to bring everyone up to date on the exciting progress on our clinical trials. As many of you are well aware, we are more than halfway done with all three clinical trials to investigate human embryonic stem cell-derived RPE cells for the treatment of dry age-related macular degeneration, or dry AMD, and Stargardt's macular dystrophy, or SMD, in the US and Europe. We have the cooperation and involvement of the best ophthalmology hospitals in the US, and some of the best eye hospitals in Europe, and the enthusiastic support of many leaders in our field. In fact, three of the investigators actually gave presentations on OUR therapy at the industry's most widely respected specialty conference. (typist note: Vail Vitrectomy). We have initiated an additional dosage 2a cohort in each of our US trials, which will enroll a total of 8 patients, 4 in each trial, with 100K RPE cells. In the new cohort, patients with better vision will receive treatment and likely have more of a photoreceptor layer to save. It is likely that for the next phase of the clinical study, patients within the cohort 2a profile will be instrumental. So we are looking forward to using this new cohort to help refine our clinical evaluations. To date, we have treated one Stargardt's patient in this new cohort, but we have scheduled one more Stargardt's and two new AMD patients just in the next couple of weeks. At this point, only two of our four US centers have received IRB approvals for the new cohort. We anticipate completing enrollment of our cohort 2a patients near the end of Q2 of this year. So if the two institutions that do not yet have IRB approval do not receive it in the next couple of weeks, we will authorize the other two sites to enroll and treat the remaining patients in the cohort. They have committed to do this.

We have observed no significant safety issues relating to our treatment and the Data and Safety Monitoring Board, or DSMB, has approved each planned step in the trial, as well as the treatment protocol for patients with better vision. We have observed the persistence of visual acuity gains and the engraftment of the transplanted cells in both the SMD and the AMD patients, which is consistent with what was previously reported on earlier in the trials. The clearance to treat patients with higher doses of RPE cells in patients and patients with greater visual acuity represents significant milestones in our clinical trials. The DSMB dose escalation analysis and approval to treat patients with better vision is very important to advancing our trials and allows us to further evaluate and target which patients may benefit the most from the treatment thereby allowing us to more appropriately define our patient population and better design the labels for our upcoming studies. Many patients, as you know, have reported improvements in their everyday lives, some having their vision improved from being able to see hand motion only to being able to read parts of an eye chart, as well as, importantly, developing better color recognition, contrast and low-light vision.

We have a meeting with our Ophthalmic Advisory Board and all of the investigators in early October and by then we will have three-month results from cohorts 2a and 3. Based on what we have seen to date, we are planning to review the data we have with our investigators, consultants, and the DSMB and will evaluate the benefit of terminating the Phase I portion of that trial, which was initially planned to treat patients with a 200K cell dose, and instead advance to a new protocol, or series of protocols, for Phase II studies. Determining the end points for Phase II of the trial will of course be critically dependent upon what we have seen from the evaluations of the cohort 2a and 3 patients, but what we have seen so far has been very tantalizing. We will likely have multiple studies in our Phase II trials. One study with mid to late-stage patients focused on visual acuity improvements, and another study of earlier stage patients looking at slowing the progression of damage associated with the disease process. Other studies may be undertaken to evaluate additional findings.

Now I want to turn to some highlights in our preclinical progress. Within ophthalmology, we have several exciting activities ongoing. In glaucoma, we have carried out studies using hES-derived retinal ganglion progenitor cells. Results in a rat model with glaucoma showed that cells had a major impact on ganglion cell survival compared to the control animals. In uveitis, preliminary studies have been carried out using hES-derived mesenchymal stem cells, or MSCs, in a mouse model of uveitis. Early data is EXTREMELY encouraging and shows the cells can prevent the disease process. In our effort to reverse blindness, we have initiated preclinical studies in rodents with rapid onset blindness using hES-derived photoreceptor progenitor cells to try to replace the already lost photoreceptors. Indeed, we have already completed studies showing we can use these cells to prevent blindness in rodents with macular degeneration. In the case of our photoreceptor progenitor cells, we are now working to isolate the factors and proteins expressed and up regulated by these cells to perhaps create a biologic or small molecule. This is the kind of therapy that could be used in later stage macular degeneration patients as a combination therapy with our RPE program.

Outside of the eye, a couple items that merit comment. In multiple sclerosis, as we have discussed before, we have a scientific paper in advanced progress. Our studies have now been repeated numerous times. hES-derived MSCs have a major impact on the clinical symptoms and neurodegeneration in the mouse model of MS. We have identified mechanisms as to why human embryonic stem cell-derived MSCs are superior to bone marrow and adipose-derived MSCs. This may have significant benefits to us. In nephropathy and hepatitis, we have trials in large animals currently underway using hES-derived MSCs to treat nephropathy and hepatitis at Tufts Veterinary school. We are also ready to initiate preclinical studies in a variety of other animal disease models using MSCs.

We have also had success outside the clinic. ACT continues to position itself to uplist from the Bulletin Board to the NASDAQ market. The recent settlement agreement with CAMOFI and CAMSHON resolved litigation associated with previously issued convertible debentures and effectively closes that chapter on the company's tortuous anti-dilutive warrant issuances. We are very close to hiring an experienced CFO. In fact, we have a handshake agreement and are now about to begin negotiating the employment agreement. We also believe that we are quite close to reaching an agreement to settle with the SEC the matters relating to certain financings that previous management executed. The next step, once the SEC matter is behind us, would be to submit a final and revised application to NASDAQ. As a clear leader in regenerative medicine, we should be trading on a major exchange. This would give more institutional investors access to our stock and provide us with greater liquidity, and the chance to appreciate in value as we meet our clinical milestones.

As we have said before, there is a great deal of interest among big pharma and biotech companies regarding joint ventures, as every major pharma company with an ophthalmology program is watching these trials very carefully. While that is exciting to us, and we know to you as well, we recognize that clinical results will drive these collaborations. With everything that has been accomplished in the clinic to date, with our corporate goals of resolving all litigation and achieving a national market listing HIGHLY obtainable, and with many exciting clinical milestones on the horizon for this year, we believe that 2013 has great potential to deliver shareholder value.

Now operator I'd like to open the call for questions.

Internet question: Who and what was the reason for coming up with the 2a study?

Gary: Okay, we designed the cohort 2a, obviously in consultation with our investigators and the Ophthalmic Advisory Board, and this was done back in October of 2012. It was done to give us data that would be useful in designing primary and secondary end points for Phase II, and its approval reflects significant confidence by the investigators, of course the DSMB, and importantly the FDA in the safety and progress of our trials.

Internet Question: Can you describe the history of what resulted in the Form 4 files?

Gary: Look, as you all know, I have been working to get this company cleaned up for the 2+ years that I have been here and this is obviously very frustrating. What I will say is that the independent members of the board are conducting a review regarding the circumstances surrounding this, as well as our internal training policies and procedures. After they have completed that review, we'll make any disclosures deemed necessary. I can't really say anything else about that now.

Jim Coon: Good afternoon Gary. Thanks for taking my call. Yeah, just good news to hear the plans on potentially terminating Phase I early and starting Phase II. So the way I understand this, OAB meets in early October to kind of look at the three-month results from the 2a cohort and the 150K cell cohort and then you decide from there where you go. So I guess my question is, from my perspective would be, you terminate Phase I, start Phase II, so from October, how long does it take to get the Phase II application submitted to the FDA and what's the expectations for how soon Phase II could potentially start?

Gary: Well, I guess what I'd say there is that first of all, we obviously have some data already on cohort 2a, as well as cohort 3; and we've seen some exciting things there. So Ed Mikunas, who is our Director of Regulatory Affairs, and the team, are already working to try to design and define what those clinical end points are. And I think you can imagine what you're looking at are two very different studies and two very different end points based on intermediate and later stage patients and improving their visual acuity as opposed to taking much earlier stage patients and trying to stem the decline of their disease. And not only is it the study itself, but it's also the follow up. So what we had originally thought, well you know, we need to figure out what label we want to go after, but after talking to the docs and seeing the results that we've seen both from now very late stage patients, as well as kind of more intermediate to late stage patients, I think it gives us confidence that you know, running contemporaneous trials would make a lot of sense. Now what's the timing for that? I mean, we're obviously not going to show up in October with a totally blank slate and say okay now let's get to work. But you know, we want to make sure that the DSMB and the investigators are signed off on this. You know, look, we've treated three patients in cohort 3 and only one in 2a. So you know, we still have 6 more patients in cohort 3 and 7 more patients in cohort 2a to treat, so we've got a lot of data to gather; but, you know, our objective is to advance to Phase II as quickly as possible. We have a lot of wind at our back. First of all, in US and Europe, the SMD trial is governed by an Orphan indication, so that gives us accelerated opportunity to be able to Fast Track, and then in the US, with dry AMD as an unmet medical need and some of the new changes that the FDA has made to Fast Tracking, we think that that puts wind at our back too. So I would rather not comment on specific timing for when we can enter Phase II, so much as to say that everything is going well for us in terms of the disease indication, the safety profile, some of the efficacy data we've seen so far, and the sort of regulatory framework behind us. So I think when you add all that up, you know, I think it would be fruitful for us to move as quickly as possible, and obviously, you know, every day that we're not in Phase II puts us a day further away from commercialization. So we're cognizant of that, while at the same time obviously having to balance, you know managing our clinical trial partners and the DSMB who justifiably is focused on making sure that we're taking all the right steps.

Michael Fields: Hi Gary. I was hoping for an overview of the MMD program at Jules Stein and an update regarding any private financing there.

Gary: You got it. Interestingly, I actually was on the phone with Dr. Schwartz today about this. We are finalizing the budget, along with Jules Stein. We want to include our other investigation centers in the trial, although for a variety of reasons, California has a lot of these patients available to us. So they are sort of finalizing some of these details with us, and our goal would be within the next two to three months to begin to start treating patients in that MMD trial. Some of the statistics that we have gleaned about MMD are simply remarkable. I mean there are large cities and countries in Asia where the incidence of MMD-related blindness is twice that of AMD-related blindness, largely because the onset of the disease is so much earlier and you're looking at a lot of people in their late 20's, 30's and early 40's that are blind as a result of this disease. So we're very, very excited about this, but finalizing the budget and making sure that it's something that we're comfortable with is important, and then Jules Stein and UCLA of course are continuing their pursuit for some additional private funding of this. Obviously the Phase I trial for this, especially if it's just done at one or two centers, is not really that expensive, and is actually baked into budget assumptions for 2013 and 2014. It's a sub two million dollar cost kind of a trial, given all the other data management and resources we have in place. So of course we would like Jules Stein to get some private funding for this. We are helping them with that, but the cost associated with it is relatively marginal.

Internet Question: When will the annual shareholders' meeting be?

Gary: You know last year we filed our proxy in relatively close coordination with our 10K. This year, we felt that we wanted to hire the CFO and settle with the SEC so that we kind of had a very clean looking company before we advance to the shareholder meeting, and we need to give about 50 to 60 days in advance notice of shareholder meeting via proxy prior to announcing the meeting, so given all the things we've got going on with the CFO and the SEC settlement, we hope to be able to get a proxy out, you know in the next month or two months kind of timeframe so that we'll be able to have a summertime annual shareholders' meeting. So we have not set a date or time, but our objective would be for it to be this summer.

Adam S: Hi Gary.

Gary: Hi Adam, how are you?

Adam: Good, how are you?

Gary: Good.

Adam: I was going to ask, in the opening remarks you mentioned the IND trialing for the platelets and I wasn't sure if there was any update on that after the pre-IND meeting with the FDA?

Gary: Yeah, we are working to identify iPS lines… so one thing that the FDA made clear to us is that you cannot test an iPS line that is not GMP into compliance. So the major providers of iPS cells do not have GMP compliant lines. So we are working now to find a provider, or potentially create a partnership, to give us iPS lines that we can use in this trial, as well as to define an indication that we can pursue -- it will be some late stage indication, so that we can demonstrate that effectively our platelets flow and participate in clot formation identically to platelets that you would find in your bloodstream. We have of course observed that in our animal studies and in our assays that we have provided. So we're working on that. Our objective is still to get that IND filed this year, but I think that given the FDA's stance on cannot test lines into GMP compliance, obviously is a big step back, really not so much for us, as it is all these iPS providers that thought that they had lines that were potentially ready for FDA review. So that's kind of where we are on that. We maintain our objective to get that filing in this year.

Internet Question: Is there any thought to getting involved in veterinary medicine since we're making excellent progress in animal trials?

Gary: The answer to that is actually yes. We have some very interesting, especially on the MSC side, but also in uveitis, and glaucoma, we have some very interesting animal models that we have looked at, including large animals, and the path to approval and revenue is much shorter in the veterinary field. So part of our preclinical study, of course involves the ability to go down the veterinary pathway, and we're taking the preliminary steps to sort of prepare the company for setting up veterinary affiliates or subsidiaries that can pursue this market. Obviously it is imperative to us, our shareholders, our stakeholders, that we maintain clear priority focus on the RPE program and those indications. But we do see some significant promise here and it is something that we will pursue.

John Rodelli: Hey Gary, do you hear me okay?

Gary: Hi John, all good.

John Rodelli: I'm doing fine. This is John Rodelli, twenty2 at investorstemcell.com. Gary it's always great to hear about the great progress at ACT. I have a two-part question if you don't mind. What is the present status regarding vision improvement for early patient Sue Freeman? How do we explain her great results? And questions No. 2. What is the status of redefinition over at the NIH? Thank you.

Gary: Okay. On your first question, we are not, by a whole variety of laws, permitted to comment on any individual patient other than to say that we continue to be impressed with the longevity of the visual acuity changes in our earliest patients, and we are working on putting together a method to present to you this long-live data and I guess we should say you should just be watching this space over the coming months for that information.

In terms of the NIH, on the last conference call we described to you how we had sort of gotten frustrated with our internal resources and some law firms that we had been using to help us pursue NIH approval. And we have hired a new consultant to help us with this and we are in dialogue with both the White House and HHS, which has purview over the NIH, about this matter and trying to break the logjam. In fact, just yesterday, I've lost track of days, just yesterday we were in the offices of Orin Hatch and Elizabeth Warren to try to advance this ball. We know that this is something that the shareholders are focused on, we are focused on it, and the reason that we are focused on it, isn't so much that we think that the NIH is going to begin actively funding our RPE program, as they are really, in a way, too far advanced for that, but we have had significant numbers of requests from collaborators that are going after a whole variety of neurological CNS disease indications that would like to use our cells, first of all because they are robust, differentiate easily, have been approved by the FDA for use in the GMP environment, and so the ability to get those cells approved could bring us significant opportunities for collaboration in Parkinson's and Alzheimer's and things like that. So this is a big, big deal to us and we are acutely involved. I guess I would say that in my 25 years as a business person, I've dealt with a lot of government agencies, both here and overseas, and in emerging markets, and this has been a very frustrating situation, and one unlike many that I've ever seen. But I do believe that we are getting to the bottom of where the issue is, and I think that we have an open-eared audience, both at HHS and the White House, to get this logjam cleared so that once and for all we can get our lines on the NIH. The irony of course is that, you know, we're the only company, the only entity that has nondestructive method of creating embryonic stem cells and you know we've been unable to get them approved. So we are bringing that argument and the logic of that argument really to both sides of the aisle and the appropriate departments within the White House and the cabinet. So, we're very focused on it and I really do hope that we'll be able to have something for you on that relatively soon.

Internet question: At what point will human embryonic stem cell RPE cells be given a trade name?

Gary: That is an excellent and timely question. We are actually working on that right now and is something that we want to get done relatively quickly, because it's a cumbersome name and it isn't reflective of how far we've advanced both the program and these cells, and all the intellectual property that we have around them. So, yeah, that is something that we are very, very focused on.

Internet question: Why haven't the two remaining IRBs okayed the trial to proceed as the others have?

Gary: I guess what I would say there is that these institutions are very large, very prestigious institutions, and while we've had no issues, there's been nothing negative that has come back, I think it is important for people to understand that in a safety trial, to go from treating patients that are legally blind to patients that still have rescuable photoreceptors and fairly significant amounts of visual acuity, is a pretty heroic leap, both on the part of the IRBs, as well as the DSMB and the FDA. So this is a process that takes time, and I think is logically being pursued methodically by these organizations, and while of course we would like everything to happen faster, we're not at all frustrated with it and we're working with these institutions to get everything cleared. We have provided all the data requested and we believe in the case of both institutions that in the next two to three weeks it will clear, but I have made clear to you what our backup plan is, which is that the other two institutions have plenty of patients and they have made it abundantly clear to me personally, as well as on a regulatory and clinical group, that they will happily do those patients, so we will continue to obviously pursue the IRBs, but our objective is to make sure these patients are done by around the end of second quarter, so if they don't come, we will absolutely do them at the other two institutions that have been approved.

Internet question: Do you see a reverse split and uplist by the end of the year?

Gary: We have made it clear that we have a significant objective this year to achieve an uplisting and to achieve a form of partnership with a large credible organization. Those are two important objectives to us. They are important objectives to the company's overall compensation program, and they are important objectives to everyone as shareholders, and we have not backed away from that one iota. So everything that we are doing is keeping in mind trying to achieve those two objectives.

We're coming up on 40 minutes here, so I'm going to wrap this up. Thank you all for your questions. We will of course be available for the second quarter earnings release, which will be in early August, and of course we have a variety of presentations and meetings before that, and will look forward to seeing you all again. Thank you all very much for your participation.

IpohMan69

So much fun with this stock   Truly a roller coaster and this will still continue for a while.....LOL

This news is from 5/15 and pay attention to the last paragraph.

http://www.reuters.com/article/2 ... panyNews&rpc=43

Investors like us anxiously wanted to know if the visual improvement of 20/400 to 20/40 is indeed true, then this morning 5/16, the company issued the press release to clear it up.

http://finance.yahoo.com/news/ac ... pant-123000456.html

IpohMan69

The ball is definitely rolling faster....I like it....LOL

http://www.dailymotion.com/video ... ll-procedure_travel

http://www.counselheal.com/artic ... ight-well-drive.htm

http://now.msn.com/blinds-mans-v ... stem-cell-treatment

http://www.upi.com/blog/2013/05/ ... ment/4261369135132/

And finally a CFO is hired, which is signalling the management is focused on bringing this company to world stage for many of us investors.

http://www.marketwatch.com/story ... -officer-2013-05-23

IpohMan69

For your eyes only.....

http://www.youtube.com/watch?v=Kn3lgskKA08

IpohMan69

Words are getting out......that vidoe in Dnews was viewed 30000 times in the first two days too.

The ball is definitely get to snowballing faster......

http://www.amd.org/our-newsletter/300-act-stem-cell.html

https://www.univercellmarket.com/@offers/news/view/3410/

http://cirmresearch.blogspot.com ... &utm_medium=twitter

http://www.counselheal.com/artic ... ight-well-drive.htm

http://now.msn.com/blinds-mans-v ... stem-cell-treatment

http://stockpick101.com/2013/05/ ... ell-technology-inc/

Below is from ACT appointed  investor relationship firm Ceocast, pay close attentionto the highlighted.

Ceocast 5/28
Advanced Cell Technology, Inc. (OTCBB: ACTC), a leader in the field of regenerative medicine, announced the appointment of Edward “Ted” Myles, CPA, as the Company’s Chief Financial Officer (CFO). This announcement was expected, as ACTC CEO Gary Rabin had previously revealed during the conference call held on May 9th that the company had reached a ‘handshake’ agreement with their CFO candidate. Edward Myles has nearly 20 years of progressive finance and operations experience in the life sciences industry. His experience in engaging the life sciences investment community and leading corporate development and operational activities will help the Company as it plans to list its stock on a national exchange and expand the shareholder base. Ed previously served as CFO of PrimeraDx, a privately-held molecular diagnostics company, which he helped lead from proof-of-concept stage to become a fully integrated commercial organization. ACTC has an exciting year ahead, having met their goals as stated so far: such as resolving the litigation regarding past warrants and debentures, moving forward with treatments in the Company’s clinical trials for AMD and SMD, and now appointing a CFO.ACTC is looking into the possibility of ending their Phase I trials early so it can advance to the next phase of clinical development. Also this summer, ACTC is looking to up-list to the Nasdaq, release more clinical data, and find the best fit for a partnership to finish clinical development of the AMD and SMD programs, moving the treatments towards commercialization.ACTC stock closed at the same price as the week prior, $0.07 a share.

IpohMan69

I am just going to quote something that I read in iCell in below, which I totally agreed; in the sense of the logic of the business world!!!

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

If I may... things do not stay the same in a fast moving market.
And ACTC's situation is a good example of what I am talking about.
There are certain partnering that ACTC could have done two years ago,
and they could not do the same today.

Two years ago, ACTC was beautiful! They have the RPEs.
Today... ACTC is 20X more beautiful... They have the RPEs, the RNPs, MSCs, Glial Progenitor Cells,
Blood, Platelets, White Cells, plus Bone Marrow.

What idiot of an Animal or a Wolf or a Shark... will not see this beauty and be stupid enough
not to swallow her?????

Two years ago... I wanted a JV, even a small one!

I still want a JV/Partnership for ACTC, but guess What?

ACTC can no longer have a small JV!

Let me explain:

If ACTC signs a small JV, she will effectively have closed the Auction.
And the companies like Roche, Novartis, and Pfizer, and Sanofi... will be free to do a TAKEOVER!

Even Rabin acknowledge the threat of a Takeover... several weeks ago.

Please note that the Threat of a Takeover is very Real! Rabin noted this himself.
And so thinking of doing a small jv will not make any sense at all!

THE ONLY OPTION LEFT FOR RABIN IS A LARGE ENOUGH JV/PARTNERSHIP THAT WILL INCLUDE A 30% TO 40% PURCHASE OF ACTC STOCKS. PEOPLE STILL THINK THAT ACTC HAS ALL THE CONTROLS... SORRY GUYS! NOT ANYMORE! THIS IS THE PROBLEM WHEN YOU DO THE AUCTION!

AN EXAMPLE OF THIS IS THE TEVA ACQUISITION AFTER THE MESOBLAST JV!

Let me explain what happened to Mesoblast.

Mesoblast partnered with Cephalon.
It was a reasonably big partnership... off the top of my head its about 2 Billion Dollars.
Then TEVA, acquired Cephalon, I think several months after the Partnership with Mesoblast.

IpohMan69

Our CSO was a keynote speaker here and these are fascinating stem cell knowledge for anyone interested. Audio on Youtube link along with Transcript included below so that it is easy for folks to listen and follow, again, courtesy of iCell member named PM1469. This is also a good way of understanding what ACTC team with the leadership of Dr. Lanza, is capable of. This is also the very reason that I am bullish on this company because their potentials is not just RPE cell therapy for Dry AMD and Stargardt's diseases, there are also a lots of other pipelines can be achieved in the future, once they get the firm footing with first JV.

http://www.youtube.com/embed/CC18PkY62mA?wmode=opaque

http://investorstemcell.com/foru ... s-media/31623-9.htm

~~~~~~~~~~~~~~~~~~~~~~~Transcripts~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Lanza, Keynote speaker at Brigham-Womens' Hospital, Boston, June 12, 2013

With the discovery of iPS technology, ACT continues to be at the forefront. They have shown that they can use protein-only transduction to generate iPS cells and have trials for neural and blood tissue development, including NIH funding for this work. His success as a stem cell biologist can be measured in many ways, as well as groups, basic and translational science, clinical trials, but also biotechnology. This is exactly why we are delighted to have him be the keynote speaker at our inaugural symposium. Thank you Dr. Lanza.

Thank you very much. I'd like to thank the organizers and in particular Paul and Rich for inviting me here. I'll be speaking to you about the use of pluripotent stem cells moving from the bench to the bedside. As you know, there are two major obstacles to regenerative medicine. The first of course is the shortage of tissue and the other is immune rejection. So with the advent of pluripotent stem cells, we now have before us, an opportunity to hopefully overcome both of those obstacles.

So there are basically two ways to make patient-specific pluripotent stem cells. The first of course is through therapeutic cloning, which basically you take a cell from the patient, put it under the zone of pellucida next to the MPA, then send an electrical charge to the unit, the DNA from the nucleus dumps into BNBA, you add some chemicals, it fools it into thinking it's fertilized, it starts to divide, and you end up with embryonic stem cells. The other approach as you know is cellular reprogramming using various transcription factors to generate iPS cells, induced pluripotent stem cells, and in both of these cases you end up with a cell that has a capacity to turn into virtually every cell type in the body.

So as you know, just a couple of weeks ago, a group for the first time generated embryonic stem cells using SCNT, or cloning. We had actually done some work. We showed that this reprogram of the nuclear genome only occurs using the human ovocyte. It does not happen with the egg, so if you put for instance a human genome or a nucleus into a cow or into a rabbit, or also if you take that same human nucleus and put it into human, in all cases you get these beautiful cleavage stage embryos, these morular embryos that look absolutely identical to a normal IVF embryo that's age match. Now the problem is that this cleavage division is driven by the maternal factors, not by the nuclear genome, so that when you look at what's going on in terms of reprogramming, these are the starting nuclear genome entities, that then grow prescription profiles, and then once you reprogram say the human nucleus of a somatic cell into a human egg, you can see this is the profile, which is almost identical to a normal age matched embryo. By contrast, even though the embryos look beautiful when you put human nucleus into the cow or the rabbit, no reprogramming at all. And if you look at the heat map here on the fourth and fifth column, virtually no reprogramming occurs.

So this is a concern of course, because obviously the use of this technology requires the use of eggs which is a serious bottleneck as human eggs are very precious. And what you actually do see with the human reprogramming is enough regulation of the various markers of pluripotency, Oct-4, SOX2 and Nanog, that sort of thing, and that is exactly why you can get iPS cells. This is what nature has evolved and that's why it works. So of course you can get these immune match cells using this technology, but the problem is again as I mentioned, there's a limited supply of eggs and it also requires the generation of embryos, which has an ethical component to that.

But of course the future of pluripotent stem cells isn't really going to be to make patient-specific cells for everybody. It turns out that there are obviously hundreds of thousands of people who have cardiovascular disease, hundreds of millions of people who have diabetes. You just can't keep making patient-specific cells for everybody. So the way this probably would work is that you would make lines that are giving you complete HLA Haplotype matches, so with 100 lines, we could match 50% of the US population, or Japan and say Korea or those kind of countries, just a handful of boot lines would do the trick. So, whether you use SCNT or iPS technology, this is an experiment we carried out that sort of shows you the power of this technology.

So these are really old cows equivalent to humans that are 70 or 80 years old, and what we did is we took a skin cell. We used nuclear transfer and we generated hematopoietic stem cells. Now because they are genetically identical to the nuclear donor, we needed to knock in a neomycin cassette so we could track the cells that we cloned. We injected these into these animals. Now normally these hematopoietic cells would not take up home in the animal without say cell divide or some way to make room in the bone marrow, but because the cells are so youthful, through competitive repopulation, they took up home in these animals very nicely. Actually it was 5 to 10-fold more competitive than adult stem cells, and we saw actually the appearance of the neomycin cassette in the blood of the animals in the first 12 weeks, and after half a year, if you took a look at the colony forming cells of these animals, about 60% of the cells were of clonal origin, and when you plated them out, you ended up with these giant white cell colonies, which you only see in very, very youthful animals. So again, this is showing you that you can actually use this technology, and because the cells are youthful, they are actually able to live in the organism quite nicely. And again, the goal here isn't just to give an old cow a new immune system. There are over 100 autoimmune diseases in humans that this kind of an approach could work with.

Here's another application. This is a cross section of a heart that had a severe myocardial infarct. This is work we actually did with Caroline Anaversa's group. So this is the healthy tissue and here is the infarcted tissue, and what we did is we injected some cloned LacZ positive cells at the margin of the infarct of a small number there, about 10,000 there, and within one month we were able to see the LacZ migrate through the infarcted tissue and actually replace 38% of the damaged infarcted tissue. So that shows you what genetically matched cells can do, for instance in those cows, allogeneic cells were rejected immediately.

So again, here now with the iPS technology, we have obviously the same way of making patient specific cells, but unfortunately, or fortunately I should say, we don't need any eggs and there are no ethical questions because no embryos are generated. So the question is are these really ready for clinical use and the problem is the original Yamanaka and Jamie Thompson methods used viral integration lente and retro viruses, and we published a paper showing initially that this caused serious problems, apoptosis, limited growth and expansion capacity and early senescence. So this is to give you an example of the problem with this technology. So you saw all these papers that came out that said you can make this cell type or that cell type, but when we tried to translate that into something that could be of medical value, we started to run into these problems with expansion. So with normal embryonic stem cells, say you want to make erythroid cells, you go through certain cycles and you can see very robust colonies or blast colonies, and by the time you finish you get a very large number of these erythroid progenitors. By contrast, when you use the iPS cells, whether it's lente virus or retro virus, much smaller colonies, less expansion, and in the end is about 1000-full difference in the expansion capacity of these viral-induced iPS cells versus normal embryonic stem cells.

Now most of those problems have been bypassed now using non-integrating methods. So we published a method using various reprogramming factors, but there are episomal methods now, messenger RNA, microRNA, and in many of those cases we now can eliminate virtually all of those problems.

So until we have patient specific cells, we're pretty limited in the application of this technology. So the initial studies are going to mainly be in the central nervous system, or the eye. And that's because these are immune privileged sites, and as I will show you, you can transplant the allogeneic cells into these sites very nicely with an attenuated immune response and no rejection of the cells.

So we focused initially in on the eye and we have multiple programs and multiple different cell types that we're creating from these pluripotent stem cells, both from embryonic stem cells and iPS cells, so our lead program using retinal pigment epithelium to treat macular degeneration and Stargardt's disease and various different retinal degenerative diseases including actually myopia. And I'll talk a little more about this.

Another program we're using hemangioblasts to treat ischemic retinopathy. We have a program where we are making entire sheets of corneal epithelium. We're working with mesenchymal stem cells to treat for instance glaucoma and uveitis. We have exciting initial data showing that these MSCs, generated from embryonic stem cells, very much attenuate uveitis. We have what's known as retinal neural progenitors, which I'll go into a little detail with you, that also has some very interesting properties. We just got fresh data in a spontaneous glaucoma rat model where we were able to rescue 50% of the damaged glial cells.

So with regard to the retinal degenerative disease program, we currently have two human clinical trials going on in the US. Again, one for dry related age-related macular degeneration, and another for Stargardt's disease, which is a leading cause of juvenile blindness. AMD as you may all know is the leading cause of blindness in the developed countries, about 30 million people worldwide have this disease. It's caused mainly by degeneration of these RPE cells, which are responsible for maintaining the health of the photoreceptors, the cones and the rods that we see with. So there is evidence of in animals and we have published some data showing that we can actually replace the damaged RPE cells with fresh ones that are made from stem cells. So this is virtually an unlimited supply of tissue that could be used for this disease.

So this is just a cartoon of the eye, just to show you what's going on, so the light comes in the eye, it hits the photoreceptors, here it comes in the rods, and underneath those are the RPE cells which have multiple functions. For instance, they provide exchange of ions. They recycle the Vitamin A. Another extremely important function is they phagocytose, they shed photoreceptor fragments, so these photoreceptors, your eyes will actually shed about up to 10% of their mass every single day, so obviously you need cells to keep that environment clean, so without these RPE, you can create a toxic environment. They also maintain Bruch's membrane. That's the membrane that the RPE sits on. And they're pigmented so they can absorb stray light and fractor some UV, so they have many, many functions. So when you lose these, this leads to a loss of your photoreceptors.

So the advantage of using pluripotent stem cells is pretty obvious. These are immortal cells, telomerase positive so that they can basically grow forever. We actually have a master cell bank that we made from one blastomere cell that could virtually treat the entire world that has this disease. So again these cells continue to grow. The cells can be grown in the laboratory under GMP conditions, completely pathogen free. They can be optimized to eliminate any variation, so the only previous way of getting RPE for treatment for this disease was from fetuses, and can you imagine getting some of these cells from the eye of a fetus and great variation from batch to batch. So you can make very large batches. One six well plate we can make enough to treat 100's of patients. And again, we can reliably make these cells from dozens of different embryonic stem cells or iPS cell lines that we have studied.

So this just shows you what goes on in the petri dish. What happens is that almost any pluripotent stem cell culture that you have will eventually start to spontaneously develop these little pigmented freckles and what will happen is that you actually remove those mechanically and plate them out, and you actually end up with cells that will start to dedifferentiate, expand, so here you see they've lost their pigmented cobblestone morphology, and then they will repopulate the dish, and then once they reach confluence, they will then reestablish the normal RPE pigmented morphology. And you can go through this dedifferentiation, differentiation cycle over and over and over, so that from a very small number of these cells you can create millions if not billions of these cells.

I would thoroughly characterize these cells in vitro, so we see a down regulation of the markers of pluripotency, so Oct-4, Nanog, and other pluripotent markers, in an up regulation of the various RPE specific markers, the Sarapin for LBP, and the likes. They look like RPE in the petri dish, so what can they actually do in animals. So we studied several different animal models. One of the gold standards in this field is known as the RCS rat, the Royal College of Surgeon rat, and we were able to show that transplantation of these human RPE cells was able to attenuate visual loss into actually, we saw 100% improvement in visual acuity over the untreated animals and actually saw the improvement in a dose-related fashion. We also studied a Stargardt's mouse model. We were able to prevent the onset of the disease process. So if you transplant these cells into a rodent model, you can actually look for say anti-human markers, so this is mitochondrial and antimitochondrial so you can see a beautiful model layer of human cells, and if you post stain it for ______, for Serapin RPE specific marker, you can see that those cells are indeed RPE cells and they line up with the mouse RPE monolayer very nicely. What I think is most impressive is when you look at the histology in terms of what these cells can do in terms of rescuing the photoreceptors. So this is the histology of the retina of RCS rat after three months. There's only one layer here, an outer nucleated layer of photoreceptors. These animals were essentially blind, but after transplantation into the subretinal space of our RPE cells, you can see this is now the outer nucleated layer, very robust, five to seven layers thick. So very significant rescue when you transplant the RPE cells.

So with that in mind, we also have developed assays for the regulatory agencies in the FDA for potency. For instance, as I mentioned, one of the major functions of RPE is phagocytosis, shed photoreceptor fragments, so we can throw latex beads into the dish and you can see that they will actually eat them and quantitate that. We've actually characterized our manufacturing process, so when you're using a pluripotent stem cell, the FDA and other regulatory agencies are mainly concerned with some trace undifferentiated cells, because again, they can become anything and you certainly don't want a hair or tooth or something in the eye or your brain, so you need to show there are no undifferentiated cells whatsoever. So our process does not allow the survival of undifferentiated cells, so what you're seeing is at the end here, even we spike the end of the manufacturing process with 10% undifferentiated embryonic stem cells, we don't end up with any undifferentiated cells in the end. We have developed an assay where we can detect even a single undifferentiated cell in over a million cells. In our clinical dose, our highest dose is about 200K cells.

We also carried out extensive safety and biodistribution studies in animals and in over 200 animals studied, we didn't see any ectopic tissue formation, no teratoma formation, and even when we spiked some of these RPE cells with say 1% undifferentiated embryonic stem cells or 0.1%, we still didn't see any teratomas versus, these are the controls, we just put in undifferentiated cells. So based on that, we got approval from the FDA to initiate two clinical trials. We have so far studied 22 patients. We are working with four of the top five eye hospitals in the United States, including Jules Stein Eye Institute at UCLA, Wills Eye Institute in Philadelphia, Bascom Palmer, which is the Number 1 in Florida, as well as Mass Eye and Ear here in Boston. And we also got approval in Europe to initiate the first study at Moorsfield Eye Hospital as well.

So the first patients were treated back in 2011 by Steve Schwartz at UCLA. So we now have about two years of data on those patients. Again, in each of these clinical trials, we have 12 patients. It's a dose escalation study. So we start with 50K and then if that's safe, we go up to 100K. We're currently now at 150K and ultimately up to 200K RPE cells. So the design is you first start with one patient. You wait six weeks. If the Data Safety Monitoring Board says it's safe, we're allowed to do the remaining two patients, and then that cycle repeats at 100K, 150K and 200K.

So early last year we published a paper in the Lancet showing the results of the first patient in each of these clinical trials. So this just shows you some of the data. The beautiful thing about working in the eye is you can look into the eye in real time and actually see what's going on. You can actually use something known as OCT and actually see down to the cellular level exactly where the cells are and what's going on, and confirms whether there is any abnormal pathology. So again, we inject the cells into a bleb in the subretinal space. This is preimplantation, and then we start seeing the appearance of the pigmentation here over time in the first three months. Then what we did is of course we measured visual acuity and a number of other parameters, and what you can actually see. First of all on OCT you can actually see the RPE attaching to Bruch's membrane. That was an important question because we weren't sure whether these would attach to an aged Bruch's membrane. But in terms of visual acuity, so we treated one of the eyes. The patient was only capable of hand motion. Couldn't read any letters on a visual acuity chart. By contrast, the operated eye that got the injection of the RPE cells, within one week the patient was able to start counting fingers. Within two weeks she could actually start counting letters. By one month she could actually count five letters on the visual acuity chart. This is a progressive disease where it actually should be getting worse and worse and it turns out that we're now almost two years and we're actually seeing continued improvement.

So we've done other patients, and again this visual acuity doesn't really measure the quality of life. These patients are now able to read their watch, they can go to the mall. They can go shopping. As a matter of fact, one of our more recent patients with the higher dose, the patient started out with a visual acuity of 20/400, well below legally blind. After an injection of the RPE cells, that patient went to 20/40, which means you can drive a car, the patient can ride a horse. So I mean these cells in theory are not supposed to actually be reversing blindness. This is basically to prevent the progression of the disease and these are indeed just safety studies, but we are obviously at this point seeing a biological signal. Many, many of the patients are reporting now unexpectedly, we weren't anticipating it, that they can see colors and blues and purples, so we're seeing some signs that these cells are having an effect, even in more advanced stage patients. We recently go approval from the FDA now to move into patients with better vision, which means there would be more photoreceptors for us to rescue.

And this just shows you that even though these are allogeneic cells, that we are not seeing rejection, here you can see the initial implantation site, no RPE cells here that are visible, and you can see within two months, and then up to six months, an increase in these RPE cells. These cells are continuing to proliferate. So obviously these cells, without immunosuppression, would have defected at this point.

So we have a number of other programs to use these pluripotent stem cells. One is for corneal repair. Actually it turns out that corneal blindness affects about 10 million people. The cornea is the most transplanted organ in humans, and more recently, instead of doing full thickness corneal transplants, the new paradigm is just to transplant the corneal epithelium on Descemet's membrane, so just the damaged endothelial cells. And we've now been able to make entire sheets of these corneal epithelium, that we're gene profiling and all the various other markers appear to be the real thing. So one of the things of course is that they need to have a tight junction, so it appears as though standing here around the nuclei here in green and similarly the ATPA skud pump here, you can see those are present as well, very similar to normal corneal epithelium. So now we're hopefully going to be putting those on some scaffolds, or thin sheets to transplant.

This is an interesting project that we did, is an interesting twist on the pluripotent stem cell story, and that is that we developed these cells known as retinal neural progenitors, and most of the times when you think about what replacement cells are going to do, they're going to replace dead cells or even vocally may have a paracrine effect, what we saw here was a more dramatic effect, which I'll describe in a second, but basically in the eye you can actually measure electrical activity very much like an eye, so there's something known as the A wave that measures the function of the cones and the rods, and then the B wave that measures the post-synaptic retinal cells. And what we were able to see is after transplantation of these retinal neural progenitors into a mouse that has a retinal degenerative disorder similar to Stargardt's disease, we were able to actually rescue that here. You can see the A wave with the retinal neural progenitors, very significant rescue of the function, and similarly we also saw this rescue over one month and two months in the B wave. And then when you look at the eye, to see what's going on, you look at the outer nucleated layer again, that's the layer with the photoreceptors, in the untreated animal here, you can see just that little black line. There's almost nothing left. These animals again are blind, but in the animals that we injected, these retinal neural progenitors, very thick layer here of the outer nucleated layer, and here it is quantitated. And that wouldn't be very exciting except that when we looked in the eye afterwards using PCR, for anti-mouse, we could see it was obviously present because these are mouse eyes, but when we looked for PCR for human tissue, there was none. So there were no cells that we transplanted into the eye, but they were having a very significant rescue. And as you can imagine, when you inject these cells into an organism, they're probably getting pulled out in the lungs and in other various tissues, so these cells were exerting over time, an endocrine effect, very distally in the body that we're rescuing these cells. So we're now using various antibody arrays to look at what proteins to spike these cells so we can look at this population of cells before it has the biological function, and then several weeks after when it does have this function and see what difference, so you can see that there are clear differences, so we can then learn from these cells as to what we would need to do to create a cocktail that may work in a patient.


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IpohMan69

So we have another cell type that has a great deal of potential known as the hemangioblast. And these are bipotential cells that early in development gave rise to the vasculature and our immune system. So they give rise to the myeloid and lymphoid lineages, as well as to the capillary and vascular cells as well. So we can take these cells and we figured out a way to make very, very large numbers of these hemangioblasts from human, both embryonic and iPS cells, and we can label them with GTS and see what they do in animals. So we did a collaboration with Maria Grant down at the University of Florida, who has an ischemia perfusion injury model where you apply pressure to the eye, you damage the retinal microvasculature, and then what you can do is you can inject these cells into the tail and you can see within 24 to 48 hours they're repairing the damaged retinal vasculature. By contrast, the contralateral eye that wasn't damaged or in control animals, there is no incorporation of these cells. So these cells are very smart. They hone to the site of injury. As a matter of fact, you can inject them intravitreally and if the eye isn't injured, they'll just sit there as a sheet.
Likewise we carried out studies to see what these cells could do in other disease models. We did a collaboration with Malcom Moore at the Sloan Kettering institute. These were animals that had ischemic limbs, so here's the hind portion of the animal. This is a Dopper flow. This is the flow, this the tail, this is the blood flow through the limbs, and you can see this animal started out with very little flow to this limb. After one injection of these hemangioblasts, within a month, we had complete restoration of the blood flow, very, very robust collateral circulation. Similarly, and again this is work with Malcom Moore, we were able to cut the death rate and mortality rate after a myocardial infarct by half. So again, these cells have significant therapeutic value.
This is a study in spontaneously diabetic type 2 rats. Again, they have the retinal damage, so you can see the hemangioblasts repairing the damaged vasculature, And as you can imagine, in diabetes, almost all the secondary complications are microvascular in nature, so these cells are almost certainly homing to other areas of the body that are injured.
So again, we have thoroughly characterized these cells. They are indeed a type of hemangioblast, EVO, TEVO positive. And as I just mentioned to you, they can make endothelial cells, uptake LDL and make these good various capillary structures. But they have, again as I mentioned, this bipotential characteristic, which means the exact same cells put into different culture conditions, instead of turning into epithelial cells, will turn into myeloid and erythroid cells. So we can then, by changing the culture conditions, instead of turning them into epithelial cells, we can turn them into entire tubes of red blood cells that are able to transport oxygen like a normal transfusable red blood cells. We can also get these cells to undergo enucleation, so that's just one of the capacities of these cells. We can actually generate both RH negative and positive blood cells. We can make Type O, B and O blood. Indeed we made several O negative lines, universal blood that can match virtually everybody in this room. So again, that is one potential application of these cells.
Another is platelets. One of the most important cells after trauma of course. And unlike red blood cells, which survive for many months, platelets only can live for a few days, so there's always a chronic shortage of the cells, they can't be frozen. So this is a very serious problem, and what we found is that we can turn going through one of these hemangiogenic intermediates, we can get huge numbers of megakaryocytes, so these are the giant multinucleated cells that are responsible for making platelets, so what that will do, is they'll start setting up these pro-platelet processes, that then break up into the platelets. So we now can get very large numbers of these platelets that undergo clot formation and retraction. We have carried out in vivo studies, where actually there is a laser-induced vascular injury where you can actually inject your cells in control platelets to see whether they incorporate into the developing thrombi, and indeed we're able to show that these pluripotent stem cell-derived platelets do indeed form these thrombi and we've got the iPS system working up and running just as nicely, if note even better than from the embryonic stem cells. And you can go into animals that have been macrophage depleteted and show that the cells basically are able to circulate just like normal blood or platelets.
So when you look at these platelets structurally, or first to say is that they're biconcaved just like normal platelets, that they're the same size as normal platelets, but at the upper structural level, you know they have the microtubules and they have all the other various microorganics such as mitochondrial, but most importantly they have alpha granules and also the dense tubular system. They also function like normal platelets, so there are a number of assays that you can do. One of them is activation on glass, and you can see like they would in a normal wound, they'll actually attach, inside the spread, so we've gone through all the various biochemical and physiological parameters and these platelets do indeed appear to be almost identical to normal platelets.
We've approached the FDA. We had a pre-IND meeting a few months ago to go into the clinic using iPS cells. They're ideal as a first indication for iPS cells because platelets don't have any nuclei, so you don't have to worry about tumor formation or teratomas. So the goal here is that these progenitors I was talking to you about to make the karyocytes, those can be frozen down very nicely. Homeland Security is very interested in this. So say there was a nuclear or radiological event; you've seen what happened here in Boston with the Marathon, but if something were to happen, you wouldn't have enough platelets. So what we can do is we could bank say millions of these progenitor to treat millions of patients, and within a few days have as many fresh platelets as we'd like.
MSCs:
Another area of great interest of course to the stem cell and regenerative medicine community are mesenchymal stem cells. These, as you all know, normally from adult tissue they are able to make bone marrow, adipose tissue. We can get them from tooth buds even, as well umbilical cord blood. So they can differentiate into blood, bone and cartilage. One of the exciting things about these cells is that they exert immunosuppressor effect. So again, these are ideal for early candidates because you can transplant an allogeneic MSC into a patient without worrying about rejection. They also migrate to the site of injury and this is part of the reason why there are so many clinical trials under way, over 200 clinical trials listed on trials.gov, and a lot of trials overseas that we don't even know about, that we've heard about. Who knows what kind of cells they have, but sometimes they're saying they're MSCs.
So why would you want to use MSCs from pluripotent stem cell source? Well the first reason of course is that you could have virtually unlimited numbers of these cells, off-the-shelf therapy. They're very, very easy to derive. They can be expanded in very, very large numbers. They're more youthful, coming from a pluripotent stem cell source, and they live a lot longer than the adult equivalent. So they have potentially greater efficacy, and I'll show you a little of that data, than the adult-derived cells. In fact, it turns out that when you try to get MSCs from say adult bone marrow and you expand it, after a few passages it serves as the great negative control, and even though it has all the same markers as an MSC, it loses its potency, so adult sources are very variable in their biological activity. But if you take a look at just the numbers, so if this is Wally that represents the number of MSCs you can get from one unit of bone marrow, if you start with the same unit from embryonic stem cell source, you can fill all of Fenway Park. So we can get over 30,000 fold greater expansion, so we can get just huge numbers of these cells, which allows us to really move intowe're now even contemplating going into horses. We can get such large numbers of these cells very, very easily. So that's great, we can get more of these cells.
MS in mouse:
We're starting to now look in various animal models. So one of the first that we looked in was the experimental autoimmune encephalitis, the DAA model. A mouse is one of the best models we have right now for multiple sclerosis. So when you induce the equivalent of MS in these animals, you have a clinical score. So when you get to 2, these animals are unable to use their forward limbs, they're paralyzed. By the time they're up to 4, they're completely paralyzed, all of their limbs are paralyzed. So what we were able to show is that we can go in with MSCs. In this particular model we're using is very aggressive, severe clinical symptoms, when you go in with bone marrow MSCs, we see minimal impact on the course of the disease. By contrast, when you go in with the MSCs derived from the embryonic stem cells, completely knocks it out. The animals have clinical scores of less than 1; in many cases almost completely normal at 0. So these animals are jumping around, you know currently with no symptoms.
We decided to look at the mechanisms here. There are certainly differences in terms of some of the cytokines, for instance, that they are releasing. We've also looked at some of the mechanisms. It turns out that bone marrow MSCs are not very good at homing, or at least getting into the damaged CNS tissue, whereas our embryonic stem cell-derived cells just very easily get into that. So getting to the site of injury is a lot easier for various reasons. I can't go into the details, but we have a paper underway here, but there are very clear mechanistic differences between MSCs derived from these various pluripotent stem cell sources.
But, there are many, many diseases you can envision using these MSCs for. As I mentioned earlier, there are over 100 autoimmune diseases that we might be able to modulate, the TNB cell function. So I just showed you some data on the multiple sclerosis, but we also have studies under way for osteoarthritis. We just got some recent data in a spontaneous mouse model of lupus. Just dramatic decrease in the mortality of these animals by using these embryonic stem cell-derived MSCs. We've got a study underway, turns out German Shepherd dogs get a disease very similar to Crohn's disease. We've got early data now with chronic pain. It turns out that these cells are able to knock out pain sensitization. We have studies underway in other diseases. For instance in liver disease, for chronic hepatitis in dogs. They develop many of the disorders that we do. And also in dogs, we're looking at kidney disease, glomerulonephritis. So again, there are a lot of diseases that these cells can impact on. I mentioned we've gotten recent data on uveitis with these MSCs where we're able to knock out the clinical development of this disease.
The exciting thing here in terms of translation is again, there is no need for immunosuppression. They persist transiently, so they only live for a few days or a couple of weeks at most. So you don't have to worry about them persisting too long forming teratomas. And we've also shown in some of our animal models that we can completely irradiate the cells and they still have a therapeutic effect.
Of course creating these various cells from the pluripotent stem cell source is only part of the problem as some of the other speakers said, we now need to learn how to recombine these, reconstitute them into more complex tissues and structures, which of course is the whole area of tissue engineering. As an example, this is a bladder that was tissue engineered by Tony Atala's group (Wake Forest) he is now in clinical trials with. And we carried out a number of years ago a collaboration with Tony where we actually took cloned renal cells that we had generated and seeded them onto these polycarbonate membranes, so this is our primitive attempt at a kidney, and this is a cow. So we took a skin cell as we described earlier. We created these renal progenitors and then what we did is we seeded them onto the scaffold, placed them under the skin of the nuclear donor animal, and if they were unseeded of course, we didn't see any fluid in the bag, so this bag represents the bladder that would collect the urine-like material. If we used unrelated or allogeneic cells that we seeded the scaffold with, we saw that the material was completely killed immunologically so there was nothing but fibrotic debris. By contrast, when you use the patient-specific cells, after three months you saw the appearance of the straw yellow material in the construct bladder, and if you looked at the histology, you would actually see that these dissociated cells had self-assembled into glomeruli and tubules, and they actually connected up here to the polycarbonate membrane in a unidirectional fashion, and when you examined the fluid here, you could actually see that they were removing toxic materials from the blood of the animal. It were actually elevated amounts of creatinine and urea. So they indeed appeared to be functioning.
So pluripotent stem cells, and in particular embryonic stem cells, the main criticism in the past has been that you have to create embryos, and the destruction of the embryo of course many people are opposed to that. So we, a number of years ago, developed a technique where, we basically borrowed the technique from the IVF clinics, which is known as PGD, where they go into an 8-cell stage embryo and they just pluck out one of the blastomeres and they use that for testing and then if the embryo is okay to implant, they allow the embryo to continue to divide and then they can then, has given rise obviously to millions of children. So we did this and we were able to show that from a single blastomere, without harming the embryo, that we were able to create these embryonic stem cell lines. So what we did was we plucked one blastomere and we allowed that to create these embryonic stem cells here, and we allowed the remaining embryo to continue to develop, so here it got to the blastocyst stage where they were frozen down, so there was no interference with the development of the embryo, and then we were able to show that the resulting embryonic stem cell lines had all the various markers of pluripotency and can turn into all three germ layers. This is teratoma formation, and so these are virtually identical to normal embryonic stem cells and no embryos were destroyed.
Finally I'd like to thank all the various people who did all the work, that get credit here for it, but in particular John Lu, Erin Kimbrel, Irina Klimanskya and a number of other people who we have collaborated with.
Rich: The retinal story is really cool. I just thought a retinal sort of regeneration model and platelets and red blood cells, they have very different cost point positions. Can you comment on how much did each patient cost for you, and do you have any hopes of..
Dr. Lanza: Yeah, so that's a really important question. I'm not even sure I'm supposed to tell you, but we can actually from a six-well plate, for the patients that were treated, $99.00 to make the dosage for one of the patients. Now, going into the clinic obviously there will be a bit of markup there.
LAUGHTER BY AUDIENCE
But I think for many of the other applications, it's going to be disease specific of course, you know to make platelets, 400 billion cells for a unit, you know we can get up into the billion range, so we need to learn how to get theseright now we can get very large numbers of the megakaryocytes, but we're using microfluidics for instance to try to increase the number of platelets each megakaryocyte can make, and if we can increase that a couple of magnitudes, we're in a position there to really make these into a dosage that will clinically impact the patients. As a matter of fact, we're planning to go into patients right now that are refractory, so there are patients right now who have developed HLA antibodies against their platelets, and they're going to die in a very few months. So if we go in with the iPS cells to make those platelets, you know we have a chance of impacting that disease. But for every disease, plateletsobviously we're not going to compete with the Red Cross any time soon, but hopefully you know, this is the Model T and eventually as we get the efficiency up, that certainly will be something that would be cost effective for various applications. But every disease is going vary.
Question: When you do the case of the macular degenerative mouse. You do this subretinal injection.
Dr. Lanza: Right.
Question: Do you see there are significant changes to the patient?
Dr. Lanza: Normally what happens is you're creating a very small bleb, and it's only a couple of hundred microliters, and then what happens is that is reabsorbed within a very few hours, so there is no
Question: And also in the case of the cornea. You showed one of the slide, the endothelial, the essential part of the cornea, but the stem cell, or progenitor cells, they happen in human eyeballs in the limbal region. Anything to do with those, the progenitor cells and endothelial. This is a difficulty that Mass and Ear, they do most of the surgery with _____, sometimes they slow the _______ and ____ control the corneal thickness and pumping into the chambers Do you see any change in the cortical thickness?
Dr. Lanza: So yes, you're actually one step ahead of us now. So we're making these sheets of cells. We did some initial studies in rabbits. The model wasn't ideal, so we're now ready to start those in a few weeks to see if that actually works.
Question: The Reuters article talked about the patient who went from 20/400 to 20/40.
Dr. Lanza, Yeah, oops. That was off the record but it got out there, yeah.
Question: Unintelligible.. something that was unique about the patient that resulted in that dramatic an increase, because the results haven't been sort of equal, I guess from all the other patients, it's 100K cell dose, right?
Dr. Lanza: Actually, the problem is, I'd be very happy to tell you all that but I almost got in trouble with the SEC by even saying that, but what I can say in general is that if there are patches of photoreceptors around to rescue, you can have a more significant impact on the visual acuity. You know, in that particular patient, there were more rather than less cells, so you know, I can't really go into the details, but the patients vary. We're seeing some of the patients that are doing really well, and other ones not as well, so there are clearly different points in the course of that disease that we're treating, and we're only treating a small region. So with the better patient visions, hopefully like I said we will have more significant areas of photoreceptors where we can impact.
Tracy, one more non-SEC filing question.
Question: Yeah, if you can answer this question, and it's related to that question about how much you're impacting human sight with the RPE injections, but in the rat also, something unexpected, you're getting beneficial effect it seems by a really unexpected mechanism. In the histology you're showing that all the photoreceptors are gone. Then you inject the RPE cells and the photoreceptors are back.
Dr. Lanza: Or, it's a progressive disease so you prevent the loss of them.
Question: You said that the RGS model rat was blind when you injected the eye.
Dr. Lanza: In the first few months, over a course of several months it goes blind, yes.
Question: So are you replacing, do you think you're stimulating endogenous stem cells?
Dr. Lanza: Yeah, so what we're doing in that case, maybe I should have been a little clearer, is that we're injecting and preventing the onset. So that when they start, we put in the RPE and we prevent the loss of photoreceptors, so we're replacing the RPE so they can maintain the health of those photoreceptors. Once those photoreceptors are gone, they're gone, although we're even doing work now where that may not be the case.
Question: With the RPC, retinal progenitor cells, you do see the replacement?
Dr. Lanza: We actually, what's interesting is that actually the progenitors in the dish want to make all the components of the eye, so if you look you can see whole cross sections in the dish on their own are photoreceptors, the _____(milner) cells, the bipolar cells. You can see even little round spheres that look like little vitreous cones looking out at you. So those progenitors can make virtually all of the components, and depending on where you pull your progenitor out, you can get them to do all sorts of tricks. So we're able to pull those cells out to do for instance just to replace the photoreceptors for instance, or to go in, whether it's a little more advanced for the RPE, or even earlier with the glial cells for glaucoma. So we really can pull off of that tree, specific cell types to do specific tricks.
Question: So you don't think you're stimulating endogenous stem cells?
Dr. Lanza: No, no. I think that is the case for many of the cells. I think for like the MSCs you clearly probably are, you know, when people thought that they were creating bone in their scaffolds, they were just stimulating endogenous stem cells. It's hard to know what these factors are doing, whether they are recruiting other things. For instance in the model where I mentioned the retinal neural progenitors, you know obviously there are signals that are going out, and whether or not they're recruiting something a little late as a result of that, I don't know yet.

IpohMan69

No news is good news, for a while, that means no issues.

But now here we are...LOL. The past July 12 came the two years mark of the first patient and there are no safety issues, no side effect with visual acuity improvement persisted.... A big WOW for me. Tell me if there is any drug based therapy in the world have that kind of track record with no side effect. The progress seems slow but we will get there, and slow is actually good for people to accumulate shares if they wanted to.....LOL.

https://eresearch.fidelity.com/eresearch/goto/evaluate/news/basicNewsStory.jhtml?symbols=ACTC&storyid=201307170830BIZWIRE_USPR_____BW5473&provider=BIZWIRE_&product=USPR____&hlinks=vnhl


ACT Secures Approval from Data Safety Monitoring Board to Complete Third Patient Cohort in All Three Clinical Trials
https://eresearch.fidelity.com/erese...__&hlinks=vnhl

07/17/2013

MARLBOROUGH, Mass.--(BUSINESS WIRE)-- Advanced Cell Technology, Inc. (ACTC) a leader in the field of regenerative medicine, announced today that the Data and Safety Monitoring Board (DSMB), an independent group of medical experts closely monitoring the company’s three ongoing clinical trials, has authorized the company to move forward with enrollment and treatment of remaining two patients in the third cohort of each of the three clinical trials. The decision follows an interim review by the DSMB six weeks after the first patient was treated in the third cohort of each trial. ACT will proceed with screening and enrollment for the patients who, in keeping with trial protocol, will be injected with 150,000 retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs).

“We are pleased that the first patients treated with the higher dose of RPE cells are doing well and the DSMB sees fit for enrollment to continue in all three clinical trials,” commented Gary Rabin, chairman and CEO of ACT. “Even with several patients failing laboratory evaluations late in the inclusion/exclusion review process, which is not atypical in clinical trials, we have four of the six patient surgeries for the third cohorts scheduled, with two remaining to complete screening. We are confident that all surgeries will be performed in ample time for a complete data review at the company’s Ophthalmic Advisory Board meeting in early October, where Phase 2 trial designs will be discussed.”

ACT’s three clinical trials in the U.S. and Europe use hESC-derived RPE cells to treat forms of macular degeneration, dry AMD and Stargardt’s Macular Dystrophy (SMD). Each trial will enroll four cohorts, with three patients each, in an ascending dosage format from 50,000 to 200,000 hESC-derived RPE cells. The U.S.-based clinical trials in AMD and SMD are currently enrolling a cohort of four patients with better vision receiving 100,000 hESC-derived RPE cells, referred to as “Cohort 2a”. To date, the company has treated four patients in Cohort 2a, with two more surgeries scheduled. These trials are prospective, open-label studies, designed to determine the safety and tolerability of hESC-derived RPE cells following sub-retinal transplantation into patients with dry AMD or SMD at 12 months, the study’s primary endpoint.
Robert Lanza, M.D., chief scientific officer of ACT, added, “The DSMB approval is an important milestone, especially as we continue to significantly increase the RPE dosage in all three of our clinical trials. This independent review of safety comes on the two year anniversary of the treatment of our first two patients in July 2011. Those original patients continue to do well, and the gains in visual acuity we first reported in The Lancet in January 2012, have persisted. We are excited to enroll the next patients in these cohorts, as well as the better vision patients in Cohort 2a of the U.S. trials.”

Preliminary results from the U.S. Stargardt’s and dry AMD trials were reported in The Lancet last year.
Further information about patient eligibility for ACT’s dry AMD study and the company’s concurrent SMD studies in the U.S. and E.U. is available at www.clinicaltrials.gov, with the following Identifiers: NCT01344993 (dry AMD), NCT01345006 (U.S. SMD), and NCT01469832 (E.U. SMD).

IpohMan69

I am sure people have doubts that if I am so bullish on this company an yet the pps is in penny land....LOL, here is one of the reasons for it. 99.99 percents of the people do not know about it or care about it, even in the medical research field. As human nature, ego plays a role to ignore the on going progress and do your own research to hope get the hoped results.

http://cnews.cari.com.my/news.php?id=422490

IpohMan69

For those that interested, you can tune in via webcast even if you are not in US. This will be 4:30am Thursday Morning in Malaysia local time.

http://finance.yahoo.com/news/ad ... ence-123000628.html

IpohMan69

Here is the transcript of the call yesterday, again courtesy of iCell member known as pm1469.

It is what I expected, no major good news or bad news but progressing steadily. You can still repay the call if you want to for two weeks.

Gary: I would like to take this opportunity to bring everyone up to date up on the exciting progress in our clinical trials. As many of you are well aware, we have been very surprised by the results of the treatments. We certainly did not expect to see visual acuity improvements in anyone in this patient set. We were resolute in our belief that there wasn't the possibility of rescuing photoreceptors at this disadvantaged stage of the disease. We are now rapidly approaching the completion of the third cohorts of all three clinical trials to investigate hESC-derived RPE cells for the treatment of dry AMD and Stargardt's macular dystrophy in the US and Europe. We continue to run our trials in the best ophthalmic hospitals in the US and the top eye hospital in Europe, and are continuing to draw the attention of leaders in the field. We are excited that we have received approval from the DSMB to complete testing on the third cohort of each of the three clinical trials after an interim review by the DSMB conducted six weeks after the first patient was treated in the third cohort of each trial. The DSMB has not had any concerns which would impede the study. In what we consider to be a resounding endorsement of the safety of our therapy, the FDA and our Data Safety Monitoring Board allowed us to treat patients with better vision as good as 20/100. These patients are likely to have more photoreceptors that can be rescued. We remain CONFIDENT THAT ALL SURGERIES ON THE REMAINING PATIENTS IN THIS GROUP WILL BE COMPLETED IN TIME FOR COMPLETE DATA REVIEW AT THE COMPANY'S OPHTHALMIC ADVISORY BOARD MEETING IN EARLY OCTOBER. This October meeting will be a chance for the company to gather with its world-renowned panel of experts around the data generated to that point. We believe this meeting will be an opportunity for us to really hone in on several strategic elements of Phase II design. We're excited to have access to the key opinion leaders in the vitreal retinal field to help us map out our path to commercialization. We have observed no significant safety issues relating to the treatment, and the DSMB has approved each planned step in the trial, as well as the treatment protocol for patients with better vision, WHICH IS NOW APPROACHING COMPLETION. We have observed the PERSISTENCE OF VISUAL ACUITY GAINS and the engraftment of the transplanted cells in both the SMD and AMD patients, which is consistent with what was previously reported early on in the trials. We just most recently treated our 26th patient. A critical part of our evaluation is to further clarify what factors will help us to identify the patients who will benefit the most. The clearance to complete treatment in patients with higher doses of RPE cells and patients with great visual acuity represented significant milestones in our clinical trials and we will be excited to share those results as soon as possible.

In summary, we have now treated 26 patients so far out of total of 35 in Cohorts 1-3, as well as special Cohort 2a. I do have to say that we anticipated treating all 35 by this time, as we discussed in our first quarter earnings call. Because I believe it is important to be candid with our investors, I want to explain this in some detail. As you are aware, AMD and SMD are enormous unmet medical needs that affect 10's of millions of people. We receive multiple calls, e-mails, faxes, and heartfelt pleas from individuals asking for access to our clinical trials. Due to regulatory requirements and our steadfast commitment to patient safety, these patients are referred to the principle investigators where they are evaluated for eligibility. We have very strict inclusion and exclusion criteria mandated by the FDA and DSMB, so obviously we cannot enroll and treat every patient that would like to participate. The complexity of the protocol and limited treatment slots does create logistical difficulties and it therefore slowed the rate at which we have been able to schedule patients for treatment. Several patients have been delayed or have been unable to continue into the treatment phase due to potential medical risk, or requirement for additional evaluation. Until such time as the additional evaluations can be completed and the patients cleared medically, it is unethical and medically inappropriate to treat these patients. Additionally, some patients cannot tolerate the immune suppression and may no longer be eligible for treatment. Unfortunately, this only becomes apparent once the process has started. This is compounded by difficulty in scheduling all patients in the summer when patients and surgeons are taking vacations.

In June, we completed gathering the information necessary for the DSMB to review and make the determination whether we can enroll our next 150K cell patients into the study. Several members of the DSMB were traveling and were logistically unable to complete their review until weeks later than expected. This forced us to miss available surgical slots in the UK in July. In the UK, August is a holiday month, so the surgery slots were not available. Now that the DSMB has provide its approval, we have these patients scheduled for treatment in September.

Separately, there is greater difficulty in recruiting better vision patients. While gaining approval to treat better vision patients was a tremendous endorsement of our safety profile by the FDA and the DSMB, there is understandably some reluctance on the part of the patients to embark on an experimental procedure. Patients with 20/100 vision are at an important crossroads in the disease. They have lost their ability to drive, but still have significant function and are therefore concerned about losing what vision they have. Despite these factors, WE ARE CONFIDENT THAT WE WILL BE ABLE TO COMPLETE COHORTS 2A AND 3 BY THE END OF SEPTEMBER, and in any case, our Ophthalmic Advisory Board WILL meet in mid October to chart the course for designing our Phase II trials. The results we are seeing lead us to question the value in Cohort 4 of the 200K cell injections. That said, we are now more confident that ever that multiple contemporaneous blebs, maybe two blebs of 100K cells each, may be an important part of our therapy. So we need to decide how to bring that into the trials. All of these variables will be addressed by the OAB in October.

To date, as I said, there have been no significant safety or tolerability issues, and trial investigators continue to be surprised and encouraged by the patients' reaction to the treatment, noting biological reaction such as engraftment of the RPE cells and improvements in patients' eyesight. The patients have seen improvements in their everyday lives, some having their vision go from being able to see movement, to being able to read parts of an eye chart, as well as reporting better color recognition; and there have been multiple reports that the patients have requested that their other eye be treated.

The company's ongoing success was even mentioned in the May 15th article in Reuters as the most promising human study using embryonic stem cells. Chief Scientific Officer Robert Lanza, MD, told the paper, which we later confirmed via press release, that a patient's vision improved from 20/400 to 20/40 after treatment with the company's RPE cells. There are many tools at our disposal to accelerate our ability to commercialize our therapy. Obviously it is premature to make any assumptions about this, but, between the advantages of our SMD Orphan Indication, and the FDA's new Breakthrough Technology Designations, we see some VERY exciting pathways. Hearing patients' stories of the remarkable quality of life improvements give us a window into TANTALIZING results and GIVES US RESOLVE THAT WE ARE ON THE PATH TO CREATING A CRITICALLY IMPORTANT REGENERATIVE MEDICINE THERAPY.

We at ACT are continually driven by a quote from Dr. Carl Kupfer, former Director of the National Eye Institute who said "In the coming years, age-related macular degeneration will take on aspects of an epidemic." WE BELIEVE THAT WE REPRESENT A REAL HOPE THAT SOMETHING CAN BE DONE ABOUT THIS DISTURBING TREND.

We have also had success outside the clinic. ACT continues to position itself to uplist from the Bulletin Board to the NASDAQ Capital Market. As you Know, we recently hired Ted Myles, an experienced Chief Financial Officer, who I expect will guide us through the next steps for listing on a major exchange. We believe that our business prospects are vastly better than our current corporate structure implies. As a leader in regenerative medicine, we feel that we should be trading on a major exchange, and once we resolve the last few legacy issues that we have discussed previously, we think we will be well positioned to complete the transformation of ACT.

There is continued interest among Big Pharma companies regarding a joint venture, or some other form of partnership, as every major pharmaceutical company with an ophthalmology program is watching these trials very carefully. While that it is exciting to us, and we know you as well, we also know that clinical results will drive those collaborations. These deals take time, and we recognize the IMPORTANCE OF PHASE II TRIAL DESIGN will play in the discussions. We expect that designing and getting clearance for our Phase II will represent an ENORMOUS VALUE CREATING MOMENT FOR ACT. Of course we look forward to sharing the data with the industry and our shareholders as soon as it is available.

Finally, in a nod to the importance we place on the thought leaders in our shareholder base, I want to express my condolences to the family of Rocky, who passed away in July. He was an important intellectual backbone to the online discourse about ACT. He never once asked an easy question of me and I really appreciated that about him. In so many ways, he was one of ACT's most engaged constituents.

Now I would like to open the call for questions.

Internet Question: Gary, what is holding up the SEC settlement and the uplisting?

Gary: Well in terms of the uplisting, obviously that's part-and-parcel to the SEC settlement; but, we have been working very diligently with the SEC, making progress. Obviously it's been slower than we hoped, but we feel that we are heading in the right path. We feel that we've got a very strong resolution to this and hope to be able to announce something relatively soon.

Internet Question: What is the status and update on scientific paper using MSCs to treat MS in rats?

Gary: That paper is working on being published right now. Both our team and our collaborators are working on it and it is, I guess you would say it is in the FINAL STAGES OF PREPARATION and then of course needs to be submitted and reviewed. Obviously an important paper for us. We believe very strongly in the future of our MSC program.

Evan Tunis: Hey Gary, thanks for taking my call. Can you explain why Advanced Cell still maintains a Corporate office in California while the CFO, Research and Development and 30 other employees are located in Mass?

Gary: Sure. For a variety of historical reasons, the company is corporate headquartered in California. We do believe in the prospect of ability to get funding in California. Our lead collaborator in the ophthalmology trials is in California, and half of our directors are here in California. So the company had a strong history in the State of California and remained here. But I really moved hard to move all of the operations from California to Marlborough, because it really helped the team work better together. And the fact that Ted is on the ground there every day is very beneficial to the inner workings of the organization. The management meetings and organization, the business development meeting and organization and just generally having all those financial resources on the ground there have really streamlined the process for everything, from payables, to analysis, to business planning. So I've been really aggressively moving all the operations to Massachusetts.

John Redaelli: Hi Gary. This is John Redaelli, twenty2 at investorstemcell.com. Always great to talk to you Gary. Thank you for taking my call. I have a couple of questions if you don't mind please. Can you please provide any details, any updates, timing regarding plans of a Rights Offering supported by existing shareholders, and would this be tied together to a future uplisting to a major market exchange like NASDAQ, or happen before. My final question, can you please update us regarding new employment contracts for you and the good Dr. Lanza. Thank you.

Gary: Okay John. Let me take them I guess in reverse order. In terms of the employment contract of Dr. Lanza, we've got the Compensation Committee working through and review of that. We've obviously begun the process and we expect to be able to sign Dr. Lanza to another contract extension. He is very happy at the company and obviously we are very fond of him as well and I expect that we will be able to get that done.

In terms of a Rights Offering, I would say that I am very favorably disposed to Rights Offerings in general. I really especially in a shareholder base like this, when we've got 47, 48,000 shareholders, it would be good, and really in the end, because of the way the Lincoln Park financing facility goes, the existing investor to a very large extent are buying the stock, they're just buying via Lincoln Park. I'm very well aware of the shareholders' interest in a Rights Offering and I will tell you that it is absolutely a part of our financial thinking in terms of designing our financial plans for the future. But, at this point I don't want to comment in anymore detail as to precisely what our plans are for doing any future finances. For now, we continue to fund ourself through Lincoln Park. It is a very attractively priced deal for us, and they have been a good partner and until we resolve the couple of open matters that still remain, we will continue to use them. But I think you can expect that taking into account the interest of our existing shareholders will be a part of future finances.

Finally, on the uplisting, obviously as part of the uplisting, NASDAQ wants us to demonstrate that we have significant capital available at our disposal and so obviously bringing in additional capital in and around the time of the uplisting will be an important part of our uplisting.

Next question please.

Jason Kolbert: Hi Guys, this is Dr. Chopat Khan. I am calling in for Jason Kolbert at Maxim. Hi Gary, hi Ted, hi Matt. I have two different questions. Can you give me your thoughts on earlier stage AMD patients versus late stage AMD patients with treatment with RPE cells?

Gary: Well, we treated three of the four early stage patients in Cohort 2a in AMD, and we are pleased with the results. I don't want to give anymore detail about that. The patient, I obviously met with and with the subject of that Reuters article, was a late-stage patient. It's very interesting, as you look at the sort of way in which these cells work, the comment that the patient that went from 20/400 to 20/40 made to me was that what was so surprising was that he woke up one morning and it was like a hole opened up in the middle of his eye, which is surprising because the normal action of this disease is that the center of your fovea, or field of vision, center field of vision, is normally where you first lose the photoreceptor function, where you first get that fuzziness and blindness, so one would have expected that this many years into the disease, those photoreceptors, which long ago stopped shedding their outer layers and stopped functioning, one would have expected that those cells would have no chance of being rescued, that they were gone, dead, cell apoptosis. So it is quite perplexing, but I saw it with my own eyes is all I can say, and it's fascinating. We as a field know very little about how long these photoreceptors can lay dormant before the cells die, and it appears to vary patient to patient based on the variety of results we have had. As you know, both of the patients have reported some visual acuity improvements, but it's variable, and so understanding how these photoreceptors function in the dormant period, how there is enough action in the remaining RPE cells to perform the phagocytic activity that's necessary for these cells to remain in place, is very new to the field and it's something that we're obviously looking at very, very carefully.

Jason Kolbert (Dr. Chopat Khan): Thanks. Second question actually is about the cost associated with manufacturing RPE. How much does it cost to actually manufacture RPE cells for each patient, each dose, and the second is, where is the manufacturing capacity at this point for moving into Phase II and Phase III?

Gary: In terms of cost, our current marginal cost of manufacturing a dose is sub $100 per dose. That is running just a single shift in the manufacturing facility in Marlborough and we currently have sufficient cells for all of Phase I and Phase II. With that said, we, as you are probably aware, are considering making a few changes. First we are talking about moving from MA09, which is an embryonic stem cell line that was derived using our single blastomere technology, but the morula was discarded after we did the cell removal. So we're talking about transferring now, bridging to the line that's called NED7. NED stands for "no embryo destroyed." In that case we also used the blastomere technique, removed a single cell, but then the embryo was frozen back down. So we're making that transition, and to the extent that we do make that transition between Phase I and Phase II, and we're working right now with the FDA on getting the approval to do that, obviously would have to manufacture a new line of cells. But the cells that we have created from NED7 to date look and act in every way identical to those from MAO9.

The other change that we're making is that we currently store the cells in a non-biocompatible media. What that means is, it's not a media that can be injected directly into humans. So on the clinical side, there has to be some cell prep where the cells are washed down and put into a fluid that's essentially like saline with some glucose in it, and injected into the patient's eyes. We have been working very aggressively, and believe we have found an answer to be able to ship the cells in a biocompatible media that we have designed, and that will cut out the cell prep and wash down required at each site, and that will make the scalability of this trial as we expand to more and more and more sites and head towards commercialization very important. So we have plenty of cells in place right now, but we may change these two particular media and the cell line that we use, for a variety of reasons, and to the extent that we do that, obviously will have to manufacture new cells.

Next question please.

Jim Coon: Good afternoon Gary, thanks for taking the call. First thing, I just want to say thanks a lot for your thoughts on Rocky. He meant a lot to a lot of the shareholder base, so we really appreciate you making a statement about him. My question basically goes back to your blog in January where you laid out kind of goals for the year, laid out 7 milestones, and I just wanted to know if you could give me a quick reading on how the company has cracked into those milestones?

Before we get into that though, the gentleman before asked the question that prompted something in me regarding the 25 patients, he was asking about improved visual acuity. Can you tell us how many of the 25 patients treated to date have seen the degeneration arrested? I know we talk about visual acuity improvements a lot, but a lot of this to me is if we can stop the degeneration and I don't hear a lot about that.

Gary: Let me address that. First of all, for a variety of reasons we don't want to give out a lot of data, because it is important to us that we have a follow-up final paper that is published in the New England Journal or the Lancet, or some very significant peer-review medical journal, and to the extent that we release too much information, the view in the community is that it's old news, so as a result they don't want to publish it. With that said, I will tell you, first of all we have treated 26 patients as of today, just so we're clear on that. We've treated 26 patients. Except in the case of patients that developed a cataract, or in the case of one patient that developed wet AMD, again a different area than where our bleb was, we have really not seen deterioration in the visual acuity of any of the patients. So that's pretty surprising from our perspective, and something we're very pleased with. This is a degenerative disease. It's a disease where you would expect a year and two years out that there would be continued degeneration. And we've been very pleased with maintaining of the visual acuity improvements that have been demonstrated across the board in patients that have seen visual acuity improvement. So that's all I really want to say.

Jim Coon: Okay good. I won't press anymore, that's great. That tells me exactly what I thought and I wanted to hear, so thank you Gary.

Gary: On the issue of the milestones, we will give you an update on the milestones. At this point, given where we are in the year, the only milestone that I am concerned about us meeting, is the uplisting, because it is simply taking longer to put this SEC matter to bed than we had expected, but I don't want to give you any guidance at this time what I believe the timing for the SEC matter is, because we are in ADVANCED DISCUSSIONS WITH THEM. Nor do I want to then speculate what the timing of the uplisting would be. But I really do feel that we will get this SEC matter put to bed IN SOME REASONABLE PERIOD OF TIME and that will hopefully, and presumably, SET OFF A CHAIN OF EVENTS THAT WILL ALLOW US TO GET THAT UPLISTING DONE.

Jim Coon: Did something happen with the SEC? I know back in February you mentioned that you thought you were in the final stages of that settlement. Is it just them dragging on or did something get in…

Gary: No. I've been asked many times does the Form 4 late filings impact the SEC? No, it's got nothing to do with it. Did a problem develop? No not at all. It is unfortunately a very methodical organization and they have many parties to this complaint, we're not the only one, and in many ways we're the small fish. So things just did not happen at the pace that our lawyers had advised us that they would.

IpohMan69

** due to word count limitation, had to split to two-part **

Jim Coon: Okay, just to follow up on the milestones on the initiation of Phase II. When you say initiation of the milestones, does that kind of mean submitting the application to the FDA? Is that feasible to get done, you know where we're at, given the way some of the injections in the 2a and Cohort 3….

Gary: I think the bigger question is what are we going to do about Cohort 4? That will color more than anything else, our submission time for Phase II. If we decide to do the 200K cell injections, or try to get a protocol change to allow us to do two 100K cell blebs, that would obviously change it. But, other than that, our goal is in October to design the Phase II trial, set the end points, and it's probably multiple trials, so that's an important part of how we're going to move forward from here.

Anthony Petrone: Hello Mr. Rabin. Thank you. When we're talking like this, does that guy who mentioned my name, does my name get out over everybody that's listening in on this?

Gary: Yes.

Anthony Petrone: So the public would know my name, so I shouldn't use my ID name on the computer, correct.

Gary: I'm not going to advise you what to do. When you say your name it is public.

Anthony Petrone: I have been with this outfit, I don't know, when they were down in the pinks, a long, long time ago before you came on, and everything you say, and everything that I've been hearing, is all promising. It's like all giggity, giggity…. I mean it's got people just…. But I've got to ask you sir, and I'm not just a nickle-dime stock holder, let me say this. A couple of million I'm proud to say, and maybe that's not a lot of money, that's not a lot to some people, but I don't know, to me that's a lot. I firmly believe in what you're doing here, what's going on, but can I ask you something, and I hope not to be redundant. Where's the money at in this? I mean you would think, where are the big dogs at, Pfizer, Merck. I mean, has anybody from ACTC kind of like had lunch with one of these guys? You know what I mean sir? Any big dogs lookin, I mean any prospects, that's what I wanted to ask you, because this all sounds exciting, all great, but where's the money.

Gary: I appreciate the fact that you have been a long-time holder in the company and we feel very optimistic about this. One thing that's important for you to understand is, and I said in my opening remarks, and I've said it at every conference that I attend, there is no big pharma or biotech company that has an ophthalmology division that doesn't know everything about these trials. This company is in Phase I. We're a Phase I biotech company. At the inflection point of value creation from the transition from Phase I to Phase II, and then from Phase II to Phase III, and then from Phase III to commercialization are ENORMOUS INFLECTIONS one can value, logarithmic jumps, and I have made it clear on every conference call, that we are not going to enter into a joint venture with what looks like the golden goose just to get 10 million dollars in the door. This is a potential multi-billion dollar therapy. And obviously we've got a long way to go from here to commercialization, but you are incorrect if you think I'm going to rush out and do a deal with one of these guys that you mention just to get a deal done. You'd be foolhardy. We've seen too much promise in this therapy to just partner it out for a small upfront payment. It would be crazy. So, I recognize what that means for shareholders is that you could be holding the stock for a while before we announce a partnership agreement, BUT THERE ARE PLENTY OF VALUE-CREATING INFLECTION POINTS BETWEEN NOW AND THEN, so that's what we're focused on.

Next caller please.

Luke Smalls: Gary, good afternoon. In the last conference call regarding the patient that went from 20/400 to 20/40, you mentioned, and I don't recall the exact words, whether it was a rare occurrence, or a freak occurrence, a couple of questions here. Do all macular degeneration patients go through the deterioration where their receptors are dormant before they die?... that's the first question. And second, what is the size of the market for people who do have dormant but not yet dead receptors? Have you been able to, accountants, been able to determine what the size of that market would be?

Gary: As I said about two questions ago, this issue of how long photoreceptors are in this dormant phase before cell death is something that very little is known about, but surprised us, the variability surprised us, and obviously it's something that we're looking at very closely, but I think as you understand, ultimately we want to be treating patients that have much better visual acuity than 20/400 and worse. We want to treat early stage patients to stem the decline of the disease. We want to treat mid stage patients to give them visual acuity improvements. So as we look at the breakdown of those patient populations, that's where we ultimately want to be. The late stage patients, it's very interesting the variability that we've seen, patient to patient in photoreceptor function after the RPE cells are injected and engrafting.

Next caller please.

Matt Faxstedder: Hi Gary. I have a question about the Cohort 2a. I apologize if this has been covered (my phone broke up). I know you can't give us any detail on the patients that have been treated thus far, but what I was wondering is there any information you can give us as far as a correlation between the late-stage patients that have already been treated and the new Cohort 2a patients? Is there any similarities in the results of those patients that you've seen thus far?

Gary: It's very early the treatment of those patients. I mean most of them have only been in for a couple of weeks. So it's premature for me to comment on that. We'll obviously talk about this more around our October meeting.

Next caller please.

Arthur Krauser: Hi Gary. I may have misunderstood the instructions, but I have another question, regarding NIH. At the last conference call, you did say that your consultant was making a lot of progress and you had had meetings with the Secretary, the cabinet officer as well as someone in President Obama's office. I'm wondering has there been any other progress? I realize they're sort of an ivory tower NIH in a sense, but has there been any progress going forward?

Gary: We have been frustrated despite our access to the highest levels of government. We have been frustrated with the pace of change at the NIH. The rules are ready to be published and the lack of publication of them has perplexed us and our consultants, despite the access we've had to senior members of Congress, Cabinet, the White House, and it's very frustrating. But we continue to push forward. And as you know, the NIH really is more about the likelihood of getting funding for people that would license or use our technology than us ourselves. We are unlikely to seek or get NIH funding for the RPE program, for example. But obviously future programs at an early stage there is the potential for, and the pace at which the NIH has been working on this has been very frustrating for us. So we've continued to push ahead. Matt, do you have any additional comments?

Matt Vincent: No, that's where it is. We regularly reach out to the folks at the NIH to see what's happening. Sometimes we get back answers, other times we don't. Each time it's a different excuse and I think we just keep pushing at it and hope that we're not too far off to actually see the new guidelines promulgated as rule.

Arthur Krauser: Okay, here's a related question. In terms of taking legal action. I know from my little bit of reading that I've done, is that government agencies are very well protected from being sued. The only people who can sue a government agency is like personal liability, like in construction someone drops a piece of metal on their toe, or something like that. But I'm wondering, you really can't sue them for dollar amounts, but I wondered if you can sue them for function. In other words, these people who want to be able to use your process are prohibited from gaining funds, or you're prohibited from gaining future funds. I just wonder if there's any legal course that you can attack them on the function end of it, that they're prohibiting you from your normal functioning or other people from normal functioning and accessing federal funds as opposed to dollar amounts. It's just that they're preventing the flow of funds from the Federal Government to these different receptors, including yourselves and other people.

Gary: Matt, can you make a very quick comment on this?

Matt: Sure, the short answer is you can go after the government for what's called Violation of the Administrative Procedures Act. I don't think we're in a position where we feel like that would be the right route here. I mean there still is an active dialogue with the folks at the NIH and a belief and an understanding that they're still trying to push this along, but are dealing with other issues related earlier this year to sequestration and just dealing with the dispatch of the Sebelius v. Shirley case. So I think litigation is always an option, but I think litigating with the government, even if there is a way to do it just is not a good option.

Patrick Curbio: Hi Gary. Thanks for taking my call. I'll be real quick. Could you give us an update on the platelet IND if things have been ironed out with that and do you expect it this year? Can you talk about the facet of doing a two 100K blebs in Cohort 4 versus Phase II, and do you anticipate an annual meeting this year? Thank you.

Gary: I'll take your questions in reverse order. We couldn't really do the two 100K blebs as part of Phase II because we would have to conduct a safe trial about it first, so it would have to be done in Phase I, but that doesn't necessarily mean that we couldn't commence Phase II, but not using obviously two separate blebs, all things that we're seriously considering and are discussing with our investigators and the independent members of our OAB.

In terms of the PLATELET IND, one of the most important things there is identifying the disease population and we are working through that, and we think our platelet program is showing great promise. We have made some very significant steps in proving the efficiency from which we can derive platelets. At first we were getting 1, 2 or 3 platelets per megakaryocyte, which is very inefficient compared to the body's close to 10,000. We're now looking like we can get that up to 30 to 50, so obviously the scaled efficiency of this is an important part of this program. We've been working on that with some people in Dr. Langer's micropyrolitic lab, and we think there is a lot of promise there. So we absolutely are spending time on it and something that we're very interested in.

Next caller please.

Fred Waldman: Gary, how are you today?

Gary: Good Fred, how are you doing?

Fred Waldman: Good. When you see that the RPEs attach to Bruch's membrane, or when you're able to get it to happen, would you say that the patient has a very good chance or you're seeing that they are seeing some vision improvement due to the fact that the cells attach to Bruch's membrane?

Gary: We've seen a lot of patients where we continue to see the proliferation of the RPE cells that we inject. Some of the other patients, I suppose those patients are showing visual acuity improvement, some not. The reason why some not, there are no photoreceptors left to rescue. So that's a little bit of the variability and get to this question of why this works for some people and not others. Why do the photoreceptors lie dormant for some people longer than others, and it's something we're obviously thinking a lot about, talking to the docs about, so it's a very important issue, no question about it. Especially if you're treating later stage patients. When you get into the intermediate stage patients, we would expect that you'll have a LOT more rescuable photoreceptors.

Fred Waldman: Obviously you can treat patients 20/100, but can you treat, if you wanted to, somebody that is 20/200 right now, or is it basically obviously the Cohort 1, 2 and 3 were 20/400 for AMD. In 2a, can you treat somebody 20/200?

Gary: Yes we can. It's 20/100 at the best. What we're trying to do is select patients that appear to have reasonably large areas with no atrophy, so being able to attack areas where we think we show promise of visual acuity improvement, and that's the trial design idea.

Next caller.

Richard Mullaro: Hi Gary. In reference to the MSC program and the platelet program. I know that you had spoke previously about some quasi-governmental funding and you did also speak about possibly getting some of these retinal progenitor cells maybe partnered out. Is there anyway that you're going to be able to get money in so you're no longer diluting shareholders? One other question, is there a possibility of doing maybe a partnership deal for a small influx of cash with clinical milestones, so you can at least get some money in the door so we're no longer diluting shareholders?

Gary: I guess I would say that we're a Phase I biotech company that has some very promising programs and we will partner the programs when we think we've got significant value from them relative to the risks that lay ahead, and the unfortunate truth about Phase I biotech companies is that they dilute shareholders. But we believe that every dollar we spend in this company will represent a VERY ATTRACTIVE RETURN on capital. So the concept of dilution to us, is we look at the long-term value proposition and believe that as we draw this capital down to 7.5 and 8 cents a share, while we obviously would rather finance at much higher prices, we believe represents VERY STRONG RETURNS on this capital. So that's the way I would approach it. Sorry, just a second. Ted, do you want to chime in there at all?

Ted: No, I think it was perfectly well phrased.

Richard Mullaro: So you haven't had any conversations with any pharmas about possible partnerships with clinical milestones, maybe like a short influx of cash on that? Can you also answer the question about the governmental, quasi-governmental funding for the platelet program? Is there is progress in that area?

Gary: We continue to talk to US and foreign government entities about significant funding opportunities for the platelet program. In terms of MSCs and the retinal progenitors, those are not governmental opportunities, those are really private sector opportunities and that is something that we are pursuing I guess you could say aggressively.

Two more calls please.

Lou Smalls: Gary, regarding the presentation that you made earlier when you said, or Ted had said there's 20 million dollars left in the Lincoln Financial line. I know you have a shelf registration for another 35 million of referred shares.

Gary: Sorry, 35 million of anything.

Lou Smalls: Okay. How long do you expect to have the cash available for the 20 million that you have and the potential of taking the additional 35 million down, which obviously would give additional dilution. How long do you expect to go through that money? In other words, what is your cash burn rate through the 20 million and then if you have to go for the next 35?

Gary: Ted, why don't you take that.

Ted: Sure. So just to clarify, the 20 million we have available under the Lincoln Park arrangement, that's secured. That's a signed deal and we have that available to us. Of course it's dependent on the stock price and with stock price stable, we expect that that money will last us more than a year at our current burn rate. As I mentioned earlier, we're certainly looking at our financing plans from a strategic and have a holistic approach. The 35 million dollar shelf registration was set up to enable flexibility so that we can pursue more permanent sources of capital and broaden our shareholder base to include long-term fundamental based institutional shareholders. We're having those discussions, but of course we feel that we want to resolve the SEC matter first and then we'll be able to get deals done with parties like that under better terms, so be able to mitigate dilution from those types of deals.

Lou Smalls. Okay, thank you very much gentlemen.

Gary: I'll take one call from the Internet then I'll take the last caller operator.

Internet question: Can you give us an update on Mr. Rabin's Form 4 transactions?

Gary: The only thing I can say is that the independent committee of the board continues to do a very thorough review of this, and as we said on the last earnings call, we will give you an update as soon as they have concluded their investigation. But they have done a very thorough job looking at documents and talking to lawyers and brokers, and so forth and they are making progress in their investigation.

Next question and this will be the last one.

John Redaelli: Hi Gary again. I want to also thank you for your kind remarks regarding the tragic loss of a great soul, Rocky. What a tremendous asset he has been for our forum at investorstemcell.com, and won't be easily replaced.

My follow-up question is regarding when you anticipate the next shareholder meeting in Palm Springs, and my final question, what progress, or what can we expect with regards of pursuing compassionate use? Thank you for taking my second call Gary.

Gary: You bet. We will have a shareholders' meeting. It will be in Palm Springs and we plan to announce something relatively soon. Obviously we are very disciplined about getting these things done. Our hope was to have everything cleaned up in time for the shareholders' meeting so that we could basically come with a plan for uplisting and we continue to strive for that, but yes we will have a shareholders' meeting and we will provide you with a date in the near future.

Your second question was about compassionate use. We are evaluating with our partner in Europe, our regulatory partner, the possibility of a Phase II pivotal trial and that's something that we're in discussions with. We have some meetings over there in September and obviously we, like you, would like to get this into compassionate use and commercialization as quickly as possible. So we're doing everything we can. As I said in my prepared remarks, we have many interesting pathways with the agencies, both because of the Orphan designation and the possibility of this Breakthrough Technology designation, and it's something that we obviously are going to aggressively pursue. We think that we have demonstrated, we've been very factful with the agencies. We've gotten all the protocol changes approved that we asked. We are treating much earlier stage patients now, which is really amazing for a Phase I trial and I think speaks volumes about what the DSMB and the FDA feel about the safety of this trial to date, and we're continuing to push forward and we remain very excited about the results that we've seen, despite the fact that this is a very early stage trial with very late stage patients. So we're very cognizant of it, but I couldn't begin to give you guidance. It's just far too early for me to speculate yet, but we're absolutely pursuing every pathway.

Gary in closing: This has been a very long quarter. We've been slogging through a lot of things. We are very excited that we feel we're about to wrap Cohort 2a and Cohort 3 and advance to this very important meeting in October. I think that that will give us a lot of things to talk about the next time that we are with you. Thank you all for spending the time. I will speak to you on the next earnings call in three months.

manofsteel

Hi, IpohMan. How many shares have you accumulate for this stock so far?! Just curious

manhattan913

Me curious too..

IpohMan69

I posted a screen shot of my account few months ago, thus you missed it..

Anyway, here is a list of some shareholders. Make your own judgement if you want to believe it or not. One thing for sure that I can tell you is I am in the list.

If you wish to add yourself to the list, please make sure you read the instruction first.

https://docs.google.com/spreadsh ... dUE&hl=en#gid=0

manofsteel

Unbelievable

IpohMan69

With 2.4 billions outstanding shares, someone got to hold something, I am one of them...LOL.

http://finance.yahoo.com/news/ad ... nary-124500118.html

Here we go again,  ACTC will try to uplist to NASDAQ, by doing a reverse split. I sure hope this will happen as it will be a lot more attractive in NASDAQ when good clinical trials results are released. The ratio now is 1:30 to 1:100. Thus after the split, using today outstanding shares of around 2.45 billions, will reduced to 80 millions shares to 24.5 millions outstanding. The company is also asking for 1 billions more authorized shares pre-split. This is understandable to me if they do not get any partnership they will need money to fund their operation by dilutive funding. Again this is a long term investment for me. Even if they get validated with partnership money, I will hold majority of my shares for the next 10 years, just sell enough to recoup my cost and pay off my current debts and have a few nice vacations....LOL. I do wish I have funding to get more shares, sound crazy eh?