√ Stem Cell Therapy Review Of Good News: Uc Davis, Asterias, Cynata, Mesoblast, Viacyte

It’s a difficult, but very important road to conclusively prove that an investigational stem cell therapy is both safe and effective in order to get selesai approval FDA or equivalents in other countries. For this reason, it is beneficial to highlight even small, but positive steps forward including encouraging pre-clinical data.

ViaCyte’s VC-01 post-implant

Today I’m doing a review of stem cell therapy good news in the clinical path with a focus on biotechs in particular (in alphabetical order), but starting first with news from here at UC Davis.

UC Davis Veterinary and Medical Schools team up in working to develop a new stem cell treatment for spina bifida with promising preclinical results in bulldogs. This great team includes veterinary surgeon Beverly Sturges, Department of Surgery Chair Diana Farmer, and stem cell researchers Aijun Wang and Dori Borjesson. See remarkable video below of the dogs and then I dive into the biotech news below that.

Asterias is expanding its SCI trial further. It announced “that Washington University School of Medicine in St. Louis, MO, has been added as a clinical site in the company’s ongoing SCiStar Phase 1/2a clinical trial of AST-OPC1, a stem-cell derived investigational therapy, in patients with severe cervical spinal cord injury (SCI).” See my recent posts on the company here.

Cynata has some stem cell good news. It reported encouraging, positive pre-clinical data in mice indicating that their Cymerus MSCs have efficacy for asthma in that model. This second pre-clinical study is a nice step forward toward future clinical trials in humans on this indication. I asked CEO Ross Macdonald about this development and here’s what I heard back:

“These preclinical data demonstrate that Cymerus™ MSCs alone or in combination with corticosteroids could provide an improved treatment option for asthma patients, without the side effects and resistance associated with steroid therapy,” said Ross Macdonald, Ph.D., Managing Director and Chief Executive Officer of Cynata Therapeutics. “We look forward to working with the Monash Lung Biology Network to complete preclinical analyses in other features of asthma, like inflammation and airway remodeling, to support a comprehensive preclinical data package and the anticipated advancement of Cymerus MSCs into clinical trials in asthma.”

Also, see my interesting chat with Macdonald from last month.

Mesoblast tells us via a PR that it sees an opportunity ahead for accelerated entry of its MPC-150-IM product for heart disease. I also asked CEO Silviu Itescu about how trials are going at the company and got this quote:

“Mesoblast is very encouraged by the progress being made in both of the Phase 2b/3 randomized controlled clinical trials using our allogeneic Stro-1/Stro-3 positive immunoselected mesenchymal precursor cells in patients with moderate/severe and end-stage heart failure. These trials build on a foundation of scientific rigor, and we hope that they will confirm the positive clinical signals seen with our technology in previously published controlled Phase 2 trials.”

See also my past posts on the company here.

ViaCyte has been getting some good press on its early trial in humans for pluripotent stem cell-based encapsulated pancreatic progenitors for diabetes. See my 2015 interview with CEO Paul Laikind. I’m showing the pic above of the ViaCyte product since I think it is so cool.

Overall, the stem cell and regenerative medicine arena remains a tough one for companies to flourish within, but these and other biotechs as well as universities like my own UC Davis are making progress in the marathon. I hope that new, in a sense experimental policy initiatives such as the FDA RMAT designation may help and not have too many downsides.

What are your favorite recent examples of stem cell good news and why?

Disclosure: I have no financial interest in any stem cell biotech and nothing here should be considered financial or medical advice.

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√ Stem Cell Good News: Spinal Cord Injury Trial, Cirm, Grants, More

Cropped Image of Jan Nolta from SacBee

Stem cell good news time…and more will be coming later this week.

The stem cell and regenerative medicine world sometimes feels chaotic because so much is going on both on the positive and negative sides of things. There is a whirlwind of activity and developments, and a tendency sometimes within our arena to just avoid bad or complicated news. One mission of this blog is to try to cover the full spectrum of developments including difficult situations, but I also want to focus in on a regular basis on what I see as good news. Below are some recent upbeat developments.

Asterias. The company announced encouraging one-year data from a small cohort of spinal cord injury patients in their clinical trial that definitely constitutes stem cell good news. Not only is their AST-OPC1 product showing a strong safety profile, but also there are continuing signs of potential indicators of efficacy including functional recovery beyond expectations of what would be seen by spontaneous recovery alone in 4 out of 6 patients. It’s still early days and this is an open label, uncontrolled study, but at this point this is very good news so far. See my interview with Asterias leadership from 10 months ago. Note that the clinical work of the company is supported in part by CIRM.

CIRM leadership. Our California stem cell agency has a new President and CEO in Maria Millan, who has been a leader at CIRM for quite some time. This is a positive step for CIRM in charting its future course. Millan replaces previous CEO Randy Mills and has been interim CEO since Mills left. Here’s more on this development from CIRM.

CIRM Grants including to UC Davis. CIRM recently has given out some important new funding including a large award to UC Davis to our Stem Cell Program to develop an Alpha Clinic here under the leadership of Jan Nolta. More from the SacBee (with picture from them of Jan above) on this. Way to go, Jan and the team!

Retina in a Dish Award. The NEI awarded a Retina Organoid challenge grant to Erin Lavik of the University of Maryland. As to the project, NEI said, “Lavik’s team proposed building a retina by screen printing 4dukt neural progenitor-derived retinal neurons in layers that mimic the structure of the human retina. The system is designed to be scalable, efficient, and reproducible, enabling high-throughput screening for drug testing.”

ViaCyte. This San Diego-area stem cell biotech also received a CIRM grant to support its work on stem cell-based therapies for diabetes, in this case specifically for high-risk Type I diabetes. I believe this privately owned company is one of the more promising regenerative medicine biotechs out there. See my past posts on ViaCyte here.

On a more individual level, my colleague Veronica Martinez-Cerdeno and I were excited that we got the cover image (above) for the latest edition of Stem Cells & Development with our recent xenotransplant hIPSC and hESC paper (more on the paper here).

What’s your stem cell good news, whether it is your own and something upbeat elsewhere in the stem cell field?

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√ Perspectives On New Stem Cells For Vision Loss Paper

Kashani, et al. Science Translational Medicine, 2018, Figure 2

Do stem cells for vision loss offer real hope?

I believe so, but it’s a long road and must be done right.

A new paper in this area generated some buzz on top of an earlier recent pub (mentioned in this post) just a week or so ago about the potential of stem cells for vision loss.

The new paper is entitled, “A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration” and is Kashani, et al.

They generated special eye cells called retinal pigmented epithelial cells or RPE from embryonic stem cells and a bio-device with the RPEs was implanted in 4 patients. RPE don’t directly function in vision (sensing light), but can help to keep other cells in the eye happier and healthier, including importantly photoreceptors.

I’m cautiously upbeat about this work for a number of reasons, but mainly because of the safety profiles and not because of any possible hints at efficacy reported.

For years, there was concern that using human pluripotent stem cells as the basis for therapies including for vision loss, even if the stem cells themselves were only used to generate differentiated eye cells for subsequent transplant and were not themselves directly part of the treatment, might be too dangerous as they have the potential to form benign but destructive tumors called teratomas. This new work along with other studies including using IPS cells point to a reassuring overall inherent safety profile so far. While there have been some adverse events, they appear to relate specifically to the procedures involved rather than the cells themselves and importantly there haven’t been tumors so far.

The major caveat with this and other similar work is that they are small, open-label studies without control groups, meaning that they do not have the power to determine if any observed potential small signs of efficacy such as hints at improved vision or halting of loss of vision are real and due to the cell therapy. So the jury is still out on stem cells for vision loss.

The clinical work led by Masayo Takahashi is still of great interest as well and is focused on using IPS cell-derived RPEs too. They have not observed tumors, but there have been challenges there that have slowed things down somewhat including the report in January of a membrane forming after introduction of stem cell product.

Another pluripotent stem cell-based effort at stem cells for macular degeneration ongoing for many years is the work led by Robert Lanza of Astellas, work that began in the company ACT and then renamed Ocata. It’s been very quiet on this front since Astellas acquired this research program. When I last communicated with Bob in May 2017, he indicated the work was very much ongoing still, but I’m hoping somehow we’ll all get another update soon.

Why has this all been so hard and time-consuming?

Beyond the challenges mentioned earlier with potential risks associated with pluripotent stem cell-based approaches that necessitate extra caution and take a lot of time, more broadly it is very challenging to translate any kind of stem cell therapy from the bench to the bedside in a responsible way that doesn’t put too much risk or financial burden on patients, and has a solid chance of efficacy. This is demanding, extremely complex research thatI’d say is harder than rocket science. Also, we have to be very careful to avoid hype.

You can see just how badly rushing unproven stem cells for eye problems at the far other end of the spectrum where unproven, for-profit stem cell clinics have sold offerings to patients, reportedly leading to retinal detachment and loss of vision (here and here).

In the long run, I think that stem cells for vision will succeed and they are going to be the basis for proven, safe therapies, but we need to do it right in terms of the research.

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√ Possible Safety Concerns From New Stem Cell, Rpe Vision Loss Study Report

With stem cells for vision loss, first we want to be sure a treatment won’t make things worse.

Several teams around the globe are rigorously studying stem cell-based approaches to vision loss via regulatory-compliant studies including for macular degeneration with some results cautiously upbeat on safety from early phase analyses, but data from a new study on the use of human embryonic stem cell (hESC)-derived retinal pigmented epithelial cells (RPEs) for macular degeneration are concerning in some ways.

Figure 1, Mehat, et al. AAO Journal 2018

The paper in the AAO Journal from a team led by James W.B. Bainbridge at UCL is entitled “Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration.”

The data here suggest that this kind of approach has some potential issues. While every stem cell study is unique, this paper also has important implications for the other studies out there using either hESC or human induced pluripotent stem cells (hIPSC) to make RPE for various forms of macular degeneration.

First, the bit of encouraging news was, “We found no evidence of uncontrolled proliferation or inflammatory responses,” which is something. You can see fundus images of the patients’ retinas in Figure 1.

However, they did not find a treatment-related improvement in vision so efficacy is not really supported so far with the analysis of the 12 patients for 13 weeks. Longer-term improvements are possible, but relatively less likely I think.

Also, there was a potential adverse event in a patient receiving the highest dose of RPEs. The authors wrote, “In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm.”

You can see supplemental Figure 3 below and note the drop in pigmented thickness in patient 10, especially as time went on in the study.

Supplemental Figure 3, Mehat, et al. AAO Journal 2018

What does this mean? It sounds like the RPE at the higher dose may have actually made the retina less healthy and impaired vision, which is worrisome, but more data are needed to be sure.

Other events are described that potentially could be concerning too including some possible immune rejection in 2 patients and ectopic RPEs in a number of patient, although the latter apparently didn’t clearly affect function:

“A reduction in the pigmentation density at the site of transplantation, evident in 2 participants (at month 6 in patient 9 and at month 12 in patient 4) may reflect rejection of pigmented donor hESC-derived RPE cells, although no associated change in retinal function was apparent.”

and

“In our study, intraocular administration of carefully obtained hESC-derived RPE cells resulted in the development of pigmented foci in the vitreous cavity in 2 participants and on the surface of the inner retina in 2 participants, suggesting reflux of donor hESC-derived RPE cells from the subretinal compartment into the vitreous cavity. Despite the presence of preretinal or intravitreal pigmentation, no associated adverse effect was evident.”

I asked Dr. Bainbridge for his perspectives on these points and the paper overall, and he had these comments:

“The hyperpigmentation is consistent with the presence of donor cell material but we have no evidence that the cells are surviving.

We are not able to biopsy the engrafted area safely to determine donor cell survival with confidence.

We were not able to detect any improvement in retinal function in the hyperpigmented areas despite detailed perimetric analysis.

Further analysis will determine whether the intervention can protect sight in the longer term.

Localised retinal thinning and reduced function may be a consequence of the natural history or the intervention.

Detailed topographical analysis of structure and function is needed to determine the safety and potential efficacy of such interventions.”

The paper ends cautiously this way:

“The evidence of safety broadly supports the rationale for further studies to explore the impact of intervention at an earlier stage of degeneration when surviving photoreceptors cells may stand to benefit with improved function and survival. However, instances of focally reduced sensitivity and thinning in hyperpigmented retina at higher doses of hESC-derived RPE cells suggest the potential for harm and indicate that intervention at earlier stages of degeneration should be approached with caution.”

Although other similar studies have reported some adverse events (e.g. see here), they seemed mostly likely to be procedural rather than cell-related. The outcomes here warrant more thought and some extra caution moving forward.

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√ Hope On Parkinson’S Front: Japan Ipsc Trial 1St Patient

In Parkinson’s Disease patients develop neurological dysfunction as they lose a special kind of brain cell called dopaminergic (or dopamine) neurons. While a number of different approaches to this disease have been studied for decades, nothing has proven particularly successful in slowing its progression. As a result there has been a big need for novel thinking about how to tackle Parkinson’s Disease including via stem cells.

One of the most exciting ideas has been to use human induced pluripotent stem cells (hIPSC) or human embryonic stem cells (hESC) to make dopamine neurons or their precursors, which would then be transplanted into the brains of patients. hIPSC-based products have the potential advantage of being an autologous or “self” transplant not requiring immunosuppression, while hESC products would likely require immunosuppression, but could have other advantages.

Fig 3i from Kikuchi, et al. Nature, 2017 focused on IPS cells derivatives for Parkinson’s in primate model.

 

A number of groups are pursuing the idea of “stem cells as a basis for treating Parkinson’s” and one, Jun Takahashi’s team in Japan, pulled the trigger (this link is to a Nature News article on this news by David Cyranoski) just weeks ago with their first trial participant.

It’s a historic moment with high hopes, but high risks too. Hope and risk often go hand-in-hand in clinical trials. Like other trials this one has a chance of either not working or of something going wrong, but I think it has a reasonable chance of success too based on the preliminary data and the solid logic behind the approach.

While the Takahashi trial was formally launched back in July, we now know that the 1st patient got transplanted in October, an important milestone. From the Cyranoski article:

“In October, neurosurgeon Takayuki Kikuchi at Kyoto University Hospital implanted 2.4 million dopamine precursor cells into the brain of a patient in his 50s. In the three-hour procedure, Kikuchi’s team deposited the cells into 12 sites, known to be centres of dopamine activity. Dopamine precursor cells have been shown to improve symptoms of Parkinson’s disease in monkeys.”

This trial is using allogeneic cells from a donor.

Other teams include that of Jeanne Loring at Scripps who is focusing on autologous IPSC-based therapies (see recent guest post by her), Lorenz Studer who is focusing on using hESC-based approaches (see my post on his talk at the annual ISSCR meeting this year in Melbourne), Roger Barker of Cambridge, and Malin Parmar at Lund University. An international collaborative group of some of these and other researchers is called GForce-PD.

You can see a cool image above of primate brain engrafted with IPS cell-derived neural precursor cells showing increased dopamine-related activity over time after the transplant in a Nature paper from last year by a team lead by Parmar and Takahashi.

We probably will know much more about the animo of this clinical trial within a year and can hope for a combination of signs of efficacy with a strong safety profile. I also am optimistic that more trials will begin in the next couple years in this area.

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