Summaries of WAFSF super stem cell vision talks: Hinton, Tsukamoto, Klassen, Takahashi

Recently I was at the World Alliance Forum in San Francisco (WAFSF), a great meeting on stem cells and regenerative medicine. WAFSF had some excellent talks and I saw one session on the use of stem cells to treat vision impairment that was particularly striking.

This session’s all-star lineup included Drs. David Hinton, Ann Tsukamoto, Henry Klassen, and Masayo Takahashi. I’m going to summarize the talks below with permission of all speakers. Note that these summaries are based on rapidly scrawled notes. Together these talks show just how far the translational stem cell vision field has come in the last few years and the very real promise for the coming years in this area for major clinical impact.

David HintonThe session began with Hinton (pictured at left in USC photo) from the Project to Cure Blindness at USC, who spoke about research on treating geographic atrophy using retinal pigmented epithelial cells (RPEs). Hinton’s stem cell device is a polarized RPE monolayer. The team places 100,000 RPEs made from human embryonic stem cells (hESC) on a parylene membrane. My impression was that they are using H9 hESC for the preclinical studies, but I’m not 100% sure.

He indicated that because of the membrane there is no significant cellular migration, but there is PEDF and VEGF secretion and the RPEs appear resistant to stress. Are the RPEs functional? It seems so as there is rhodopsin phagocytosis.

For the studies he discussed, they used the RCS rat model of retinal degeneration of which there was a partial rescue by hESC-RPEs and encouragingly from a safety perspective, no teratomas.

Surprisingly, control parylene alone without cells has some rescue function, but with RPE there was substantially better organization and electrical function. One kind of cool thing from a techno perspective is that they invented a special delivery tool that gently folds the RPE sheet for insertion into the eye upon which it unfolds. It looked like it worked like a charm based on a video shown.

What does the future hold for this project?
They hope to file an IND within a few months and the target for starting a clinical trial is 2015. There was a question from audience on IP navigation. They have a license deal with WARF and they are aware of the ACT patents (now known as Ocata Therapeutics), which presumably will need to be addressed in some fashion such as licensing. Another question was on residual undifferentiated ESC. Shouldn’t be a problem, he said, because the special media that they use causes ESC death.


The next talk was from Ann Tsukamoto of StemCells, Inc.

They are studying the use of human CNS stem cells for treating dry eye AMD. These cells are called HuCNS-SC. After transplantation in mice the cells engraft and migrate. In RCS rats there is loss of RPEs and then 2ndary loss of photo receptors. HuCNS-SC transplanted at P21 migrate well (there’s no matrix). With transplant of HuCNS-SC they see maintenance of photoreceptors and visual acuity. What is the mechanism?

Ann Tsukamoto
One is suggested by the observation that the cells have phagocytosis function and debris is absent. They hypothesize that as a result there is preservation of synaptic connections. They have a combined phase I/II trial going, which includes a 3-month immunosuppression regimen. They have done 6-12-month follow up on 7 patients and found encouragingly no cell-related safety concerns. Best corrected visual acuity (BCVA) improved in 2 study eyes, but also in 1 control eye. They found that 6/7 treated eyes had 70% reduced geographic atrophy. I’m curious to see how this work goes as it continues to develop. HuCNS-SC may have utility to treat other diseases as well.
Henry Klassen                                                   Henry Klassen from the Gavin Herbert Eye Institute at UC Irvine spoke next (photo from UCI). Klassen’s team is studying the use of fetal retinal progenitor cells (RPC) for treating retinitis pigments (RP).
In RP there is loss of photoreceptors and loss of cones by bystander effect, Klassen said. Because of the importance of cones, the goal is to try to rescue them. This team produced their stem cell-based product here at UC Davis in the GMP facility. The RPCs, which are not immunogenic, are injected into the vitreous. They used the same RCS rat model as the first two speakers. They transplant the RPC as a single cell suspension but cells aggregate after transplant into neurospheres that float around in the vitreous and secrete cytokines. It’s like a floating pharmacy (my analogy). They observed that the RPCs rescue rods and cones in rat.
Their goal is to have an IND before the end of the year. They have done the work in part with funding from CIRM and interestingly have founded a company called jCyte. One pretty neat additional point was that this therapy has the potential for treating AMD too and would be complimentary with other types of therapies such as those mentioned by the first two speakers. I didn’t have a have chance, but I had hoped to ask Klassen if they thought that patients would be able to see (or not) the neurospheres like little floaters in the eye.


Masayo TakahashiThe final speaker of the session was Stem Cell Person of the Year, Masayo Takahashi, from RIKEN. She spoke about using RPEs made from human induced pluripotent stem cells (IPSC). She discussed treating wet AMD with the RPEs. I understood that to make IPSC they used the episomal vector approach.

They started with 24 IPSC lines, then picked the top 6 and then 3 of those lines were used to make the RPEs using a 4-month differentiation period. Of the original 6, it was notable that despite using an episomal vector, in one there was a plasmid remnant. So for all you folks out there using “transient”, “non-genetic” methods, one lesson here is to be sure to do the needed testing and validation of human IPSC lines.

They then pick pigmented clones and made sheets. It’s a lengthy and expensive process with one of the biggest expenses being the facility itself, which costs ~$500K/year just to run.

For safety testing and validation, they did their Lin28 PCR assay for residual IPSC as well as whole genome sequencing. In addition, no tumors were observed.

The RPE product, a 1.3 x 3 mm wide device, was just transplanted recently into the first human AMD patient. I think everyone is on the edge of their seat in this field to see how this clinical study progresses.

Looking to the future, Takahashi mentioned that allogeneic transplantation is an option and teams are moving in that direction. An IPSC cell bank with a variety of HLA types could be helpful to many patients in an allogeneic manner.

She also discussed the regulatory situation in Japan including the novel concept of adaptive licensing (see below the overview of the current regulatory system in Japan).

Japan stem cell regulatory system

She mentioned that it is a fast system, but acknowledged that it has risks too. She also said they are planning photoreceptor transplantation in 5 years for RP.

Overall these four talks were very encouraging for the future of treating various forms of vision impairment using stem cells.

Encouraging New Paper on ACT Stem Cell-Based Trial for Macular Degeneration

The stem cell biotech Advanced Cell Technology (ACT) reported new, positive data in a paper in Lancet from their clinical trials using retinal pigmented epithelial cells (RPEs) made from human embryonic stem cells (hESC) for treatment of different forms of macular degeneration (MD).

The paper was entitled “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies” with first author Steven D. Schwartz and senior author Robert Lanza, CSO of ACT.

These two trials (one each for Stargardt’s MD and age-related MD (AMD) with 9 treated patients each) are combined prospective phase 1/2 studies. The primary goal of these trials is to assess drug safety. Importantly so far no major adverse outcomes were reported, but some adverse side effects appeared related to the procedure itself and to immunosuppression so those must be kept in mind. As to the latter, in theory an autologous induced pluripotent stem cell (IPSC)-based therapy could be superior in terms of likely not needing immunosupression, but there may be practical advantages to an hESC-based therapy in other ways (e.g. lower cost).

A potential major bonus here in the ACT report today is that despite the fact that the trial used relatively low doses of cells and despite the primary measure here being safety, ACT reported in this publication that a substantial number of the patients also had measurable improvements in their vision:

Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt’s macular dystrophy.

This is a very positive, even if somewhat surprising development in terms of potential efficacy. The main cause of vision impairment in MD is not thought to be loss of RPEs, but rather photoreceptor cells. So how could transplanted RPEs (and relatively low cellular doses for the most part at that) potentially improve vision? The working theory seems to be that the RPEs might help remaining photoreceptors stay alive, healthier, and perhaps more properly functional.

ACT FIgure 1

I thought it was notable that 72% of the transplant recipients had measurable increases in subretinal pigmentation and pigmentation gradually increased over time, indicative of a high-rate of stable engraftment of the RPEs (see image above from Figure 1).

The authors summarized their interpretation of their results in this way:

Our study provides the first evidence of the medium-term to long-term safety, survival, and possible biological activity of pluripotent stem cell progeny after transplantation in people with any disease. The results suggest that human-embryonic-stem-cell-derived cells could provide a potentially safe new source of cells for the treatment of various medical disorders that require tissue repair or replacement.

I’ll be very curious to see the future results as ACT likely begins to treat patients with higher doses of cells and patients with relatively earlier (potential more treatable) stages of MD.

In the wider scheme of things, ACT’s results are also encouraging for other stem cell biotechs and other similar kinds of studies. For example, it will be interesting to see how the IPSC-based RPE clinical study in Japan for MD proceeds and how the BioTime subsidiaries (1) Asterias’ hESC-based trial for spinal cord injury and (2) Cell Cure’s hESC-based trial for AMD proceed. There can perhaps be greater hope of safety for these other vision-related pluripotent stem cell-based trials as well now and also for other studies such as ViaCyte’s hESC-based trial for Diabetes, which may start very soon.

Still, it’s relatively early days and these kinds of endeavors are risky marathons rather than sprints, so quite a lot of caution is in order.

Disclosure. The author has a small, long-term stock position in ACT. This post is not intended to be financial or health advice. Consult your financial advisor and doctor (not blogs) for making those kinds of important decisions.

ACT’s Bob Lanza Does the #IceBucketChallenge

Before I did the #icebucketchallenge, I challenged the leader of Advanced Cell Technology (ACT), Dr. Bob Lanza, to do the Ice Bucket Challenge.

He did it and leading up to it he provided a quite articulate message for context (see video below). Bob is one very cool guy even without ice water.

Bob nominated ACT scientists Irina Klimanskaya, Shi-Jiang (John) Lu, and Erin Kimbrel to go next.

Where I Do The Ice Bucket Challenge & Who Did I Challenge?

Paul  ice bucket challengeI was challenged to do the Ice Bucket Challenge by Roman Reed.

I did it yesterday and can see it was mighty cold! Total shock, but fun. It sure wakes you up. Yeah, we have a drought but I did the big splash with tons of ice.

I did the challenge in honor of patients with ALS and the ALS Foundation, patients with Spinal Muscle Atrophy (SMA) and the Gwendolyn Strong Foundation, and the St. Baldrick’s Foundation for children’s cancer research. I’ve already given to St. Baldrick’s and shaved my head this year for the third year in a row. I’ll be giving donations to the ALS and Gwendolyn Strong Foundations. Please consider giving as well.

In my video (below) I challenge Robert Lanza of Advanced Cell Technology (ACT) to do the challenge too. What do you say, Bob?

Interview with Bob Lanza on new ACT stem cells for MS paper

Robert-LanzaI did a brief email Q&A interview with Dr. Bob Lanza of Advanced Cell Technology (ACT) on their new hES-MSC pre-clinical data for Multiple Sclerosis. I discussed the paper itself in a concise review yesterday here.

Thanks to Dr. Lanza for doing the interview.

1. Were you surprised at the fact that the therapeutic benefit did not require engraftment or even the use of proliferative hES-MSCs?

No, not at all.  MSCs usually persist for only a few days or weeks, and exert their therapeutic effects during that short time period     

2. Any thought on the mechanism by which the hES-MSCs are beneficial? Trophic factors?

MSCs have myriad functions.  They can, of course, modulate B and T cell function and impact the autoimmune process itself.  But extravasation also seems to be very important, so release of trophic factors at the local site of inflammation and damage may also be a critical part of the mechanism by which they are beneficial.  

3. Why inject intraperitoneally? Have you done any studies based on IV injection or direct transplantation into the CNS itself?

The cells have homing receptors and migrate to the site of injury regardless of the route of administration.  Although we haven’t looked at it in this particular model, IV works quite well in the other autoimmune models we’ve examined.  I suspect direct transplantation into the CNS itself would work equally well, if not better.  However, that would obviously be a less desirable route for clinical application.   

4. What are the steps between where these studies stand today and getting a therapy based on this product into clinical trials?

We need to complete IND enabling studies—i.e. dosage, safety, tumorigenicity, and biodistribution studies etc.