Stem cell-derived retinal patch continues to show promising results two years post-implantation

Earlier this year we wrote about the promising results of a phase 1 clinical trial aimed at replacing the deteriorating cells in the retinas of people suffering from age-related macular degeneration- one of the leading causes of blindness worldwide for people over 50. Now there’s even more good news! Highlighted in a news story on the UC Santa Barbara (UCSB) website, researchers are continuing to make progress in their bid to secure approval from the Food and Drug Administration for the life-changing treatment.

Through the collaborative efforts of researchers at UCSB, University of Southern California and California Institute of Technology, a stem cell-derived implant using cells from a healthy donor was developed. The bioengineered implant, described as a scaffold, was then implanted under the retina of 16 participants. If the implant was to work, the new cells would then take up the functions of the old ones, and slow down or prevent further deterioration. In the best-case scenario, they could restore some lost vision.

The first sets of trials, funded by the California Institute for Regenerative Medicine (CIRM), concentrated on establishing the safety of the patch and collecting data on its effectiveness. Parting ways with old practices, the participants in the trial were given just two months of immunosuppressants whereas in the past, using donor cells meant that patients often had to be given long-term immunosuppression to stop their body’s immune system attacking and destroying the implanted cells. The team found that after two years, the presence of the patch hadn’t triggered other conditions associated with implantation, such as the formation of new blood vessels or scar tissue that could cause a detachment of the retina.

Even more importantly, they found no sign of inflammation that indicated an immune response to the foreign cells even after the patient was taken off immunosuppressants two months post-implantation. “What really makes us excited is that there is some strong evidence to show that the cells are still there two years after implantation and they’re still functional,” said Mohamed Faynus, a graduate student researcher in the lab of stem cell biologist Dennis O. Clegg at UCSB.

Having passed the initial phase, the team of researchers now hopes to begin phase 2 of the trial. This time, they are aiming to more specifically assesses the effectiveness of the patch in participants. Looking even farther ahead, the Clegg Lab and colleagues are also exploring combining multiple cell types on the patch to treat patients at varying stages of the disease.

In addition, there have also been improvements made to extend the shelf life of the patch. “Cryopreservation of the therapy significantly extends the product’s shelf-life and allows us to ship the implant on demand all over the world, thus making it more accessible to patients across the globe,” said Britney Pennington, a research scientist in the Clegg Lab.

How a tiny patch is helping restore lasting vision

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Researchers are working on a stem cell-based retinal implant that could be used for people with with advanced dry age-related macular degeneration. (Photo/ Britney O. Pennington)

When Anna Kuehl began losing her vision, she feared losing the ability to read and go on long walks in nature—two of her favorite pastimes. Anna had been diagnosed with age-related macular degeneration, the leading cause of vision loss in the US. She lost the central vision in her left eye, which meant she could no longer make out people’s faces clearly, drive a car, or read the time on her watch.

Anna Kuehl

But a clinical trial funded by the California Institute for Regenerative Medicine  (CIRM) helped change that. And now, new data from that trial shows the treatment appears to be long lasting.

The treatment sprang out of research done by Dr. Mark Humayun and his team at USC. In collaboration with Regenerative Patch Technologies they developed a stem cell-derived implant using cells from a healthy donor. The implant was then placed under the retina in the back of the eye. The hope was those stem cells would then repair and replace damaged cells and restore some vision.

Dr. Mark Humayun, photo courtesy USC

In the past, using donor cells meant that patients often had to be given long-term immunosuppression to stop their body’s immune system attacking and destroying the patch. But in this trial, the patients were given just two months of immunosuppression, shortly before and after the implant procedure.

In a news story on the USC website, Dr. Humayun said this was an important advantage. “There’s been some debate on whether stem cells derived from a different, unrelated person would survive in the retina without long-term immunosuppression. For instance, if you were to receive a kidney transplant, long-term immunosuppression would be required to prevent organ rejection. This study indicates the cells on the retinal implant can survive for up to two years without long-term immunosuppression.”

Cells show staying power

When one of the patients in the clinical trial died from unrelated causes two years after getting the implant, the research team were able to show that even with only limited immunosuppression, there was no evidence that the patient’s body was rejecting the donor cells.

“These findings show the implant can improve visual function in some patients who were legally-blind before treatment and that the cells on the implant survive and remain functional for at least two years despite not being matched with those of the patient,” Humayun said.

For Anna Kuehl, the results have been remarkable. She was able to read an additional 17 letters on a standard eye chart. Even more importantly, she is able to read again, and able to walk and enjoy nature again.

Dr. Humayun says the study—published in the journal Stem Cell Reports—may have implications for treating other vision-destroying diseases. “This study addresses the debate over the viability of using mismatched stem cells — this shows that a mismatched stem cell derived implant can be safe and viable over multiple years.”

Sometimes a cold stare is a good thing

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in the elderly in the U.S. It’s estimated that some 11 million Americans could have some form of the disease, a number that is growing every year. So if you are going to develop a treatment for this condition, you need to make sure it can reach a lot of people easily. And that’s exactly what some CIRM-supported researchers are doing.

Let’s back up a little first. AMD is a degenerative condition where the macular, the small central portion of your retina, is slowly worn away. That’s crucial because the retina is the light-sensing nerve tissue at the back of your eye. At first you notice that your vision is getting blurry and it’s hard to read fine print or drive a car. As it progresses you develop dark, blurry areas in the center of your vision.

There are two kinds of AMD, a wet form and a dry form. The dry form is the most common, affecting 90% of patients. There is no cure and no effective treatment. But researchers at the University of Southern California (USC), the University of California Santa Barbara (UCSB) and a company called Regenerative Patch Technologies are developing a method that is looking promising.

They are using stem cells to grow retinal pigment epithelium (RPE) cells, the kind attacked by the disease, and putting them on a tiny synthetic scaffold which is then placed at the back of the eye. The hope is these RPE cells will help slow down the progression of the disease or even restore vision.

Early results from a CIRM-funded clinical trial are encouraging. Of the five patients enrolled in the Phase 1/2a trial, four maintained their vision in the treated eye, two showed improvement in the stability of their vision, and one patient had a 17-letter improvement in their vision on a reading chart. In addition, there were no serious side effects or unanticipated problems.

So now the team are taking this approach one step further. In a study published in Scientific Reports, they say they have developed a way to cryopreserve or freeze this cell and scaffold structure.

In a news release, Dr. Dennis Clegg of UCSB, says the frozen implants are comparable to the non-frozen ones and this technique will extend shelf life and enable on-demand distribution to distant clinical sites, increasing the number of patients able to benefit from such treatments.

“It’s a major advance in the development of cell therapies using a sheet of cells, or a monolayer of cells, because you can freeze them as the final product and ship them all over the world.”

Cool.

Two voices, one message, watch out for predatory stem cell clinics

Last week two new papers came out echoing each other about the dangers of bogus “therapies” being offered by predatory stem cell clinics and the risks they pose to patients.

The first was from the Pew Charitable Trusts entitled: ‘Harms Linked to Unapproved Stem Cell Interventions Highlight Need for Greater FDA Enforcement’ with a subtitle: Unproven regenerative medical products have led to infections, disabilities, and deaths.’

That pretty much says everything you need to know about the report, and in pretty stark terms; need for greater FDA enforcement and infections, disabilities and deaths.

Just two days later, as if in response to the call for greater enforcement, the Food and Drug Administration (FDA) came out with its own paper titled: ‘Important Patient and Consumer Information About Regenerative Medicine Therapies.’ Like the Pew report the FDA’s paper highlighted the dangers of unproven and unapproved “therapies” saying it “has received reports of blindness, tumor formation, infections, and more… due to the use of these unapproved products.”

The FDA runs down a list of diseases and conditions that predatory clinics claim they can cure without any evidence that what they offer is even safe, let alone effective. It says Regenerative Medicine therapies have not been approved for the treatment of:

  • Arthritis, osteoarthritis, rheumatism, hip pain, knee pain or shoulder pain.
  • Blindness or vision loss, autism, chronic pain or fatigue.
  • Neurological conditions like Alzheimer’s and Parkinson’s.
  • Heart disease, lung disease or stroke.

The FDA says it has warned clinics offering these “therapies” to stop or face the risk of legal action, and it warns consumers: “Please know that if you are being charged for these products or offered these products outside of a clinical trial, you are likely being deceived and offered a product illegally.”

It tells consumers if you are offered one of these therapies – often at great personal cost running into the thousands, even tens of thousands of dollars – you should contact the FDA at ocod@fda.hhs.gov.

The Pew report highlights just how dangerous these “therapies” are for patients. They did a deep dive into health records and found that between 2004 and September 2020 there were more than 360 reported cases of patients experiencing serious side effects from a clinic that offered unproven and unapproved stem cell procedures.

Those side effects include 20 deaths as well as serious and even lifelong disabilities such as:

  • Partial or complete blindness (9).
  • Paraplegia (1).
  • Pulmonary embolism (6).
  • Heart attack (5).
  • Tumors, lesions, or other growths (16).
  • Organ damage or failure in several cases that resulted in death.

More than one hundred of the patients identified had to be hospitalized.

The most common type of procedures these patients were given were stem cells taken from their own body and then injected into their eye, spine, hip, shoulder, or knee. The second most common was stem cells from a donor that were then injected.

The Pew report cites the case of one California-based stem cell company that sold products manufactured without proper safety measures, “including a failure to properly screen for communicable diseases such as HIV and hepatitis B and C.” Those products led to at least 13 people being hospitalized due to serious bacterial infection in Texas, Arizona, Kansas, and Florida.

Shocking as these statistics are, the report says this is probably a gross under count of actual harm caused by the bogus clinics. It says the clinics themselves rarely report adverse events and many patients don’t report them either, unless they are so serious that they require medical intervention.

The Pew report concludes by saying the FDA needs more resources so it can more effectively act against these clinics and shut them down when necessary. It says the agency needs to encourage doctors and patients to report any unexpected side effects, saying: “devising effective strategies to collect more real-world evidence of harm can help the agency in its efforts to curb the growth of this unregulated market and ensure that the regenerative medicine field develops into one that clinicians and patients can trust and safely access.”

We completely support both reports and will continue to work with the FDA and anyone else opposed to these predatory clinics. You can read more here about what we have been doing to oppose these clinics, and here is information that will help inform your decision if you are thinking about taking part in a stem cell clinical trial but are not sure if it’s a legitimate one.

Cures, clinical trials and unmet medical needs

When you have a great story to tell there’s no shame in repeating it as often as you can. After all, not everyone gets to hear first time around. Or second or third time. So that’s why we wanted to give you another opportunity to tune into some of the great presentations and discussions at our recent CIRM Alpha Stem Cell Clinic Network Symposium.

It was a day of fascinating science, heart-warming, and heart-breaking, stories. A day to celebrate the progress being made and to discuss the challenges that still lie ahead.

There is a wide selection of topics from “Driving Towards a Cure” – which looks at some pioneering work being done in research targeting type 1 diabetes and HIV/AIDS – to Cancer Clinical Trials, that looks at therapies for multiple myeloma, brain cancer and leukemia.

The COVID-19 pandemic also proved the background for two detailed discussions on our funding for projects targeting the coronavirus, and for how the lessons learned from the pandemic can help us be more responsive to the needs of underserved communities.

Here’s the agenda for the day and with each topic there’s a link to the video of the presentation and conversation.

Thursday October 8, 2020

View Recording: CIRM Fellows Trainees

9:00am Welcome Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director  

Catriona Jamieson, MD,  View Recording: ASCC Network Value Proposition

9:10am Session I:  Cures for Rare Diseases Innovation in Action 

Moderator: Mark Walters, MD, UCSF, ASCC Program Director 

Don Kohn, MD, UCLA – View Recording: Severe combined immunodeficiency (SCID) 

Mark Walters, MD, UCSF, ASCC Program Director – View Recording: Thalassemia 

Pawash Priyank, View Recording: Patient Experience – SCID

Olivia and Stacy Stahl, View Recording: Patient Experience – Thalassemia

10 minute panel discussion/Q&A 

BREAK

9:55am Session II: Addressing Unmet Medical Needs: Driving Towards a Cure 

Moderator: John Zaia, MD, City of Hope, ASCC Program Direction 

Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director – View Recording: HIV

Manasi Jaiman, MD, MPH, ViaCyte, Vice President, Clinical Development – View Recording: Diabetes

Jeff Taylor, Patient Experience – HIV

10 minute panel discussion/Q&A 

BREAK

10:40am Session III: Cancer Clinical Trials: Networking for Impact 

Moderator: Catriona Jamieson, MD, UC San Diego, ASCC Program Director 

Daniela Bota, MD, PhD, UC Irvine, ASCC Program Director – View Recording:  Glioblastoma 

Michael Choi, MD, UC San Diego – View Recording: Cirmtuzimab

Matthew Spear, MD, Poseida Therapeutics, Chief Medical Officer – View Recording: Multiple Myeloma  

John Lapham, Patient Experience –  View Recording: Chronic lymphocytic leukemia (CLL) 

10 minute panel discussion/Q&A 

BREAK

11:30am Session IV: Responding to COVID-19 and Engaging Communities

Two live “roundtable conversation” sessions, 1 hour each.

Roundtable 1: Moderator Maria Millan, MD, CIRM 

CIRM’s / ASCC Network’s response to COVID-19 Convalescent Plasma, Cell Therapy and Novel Vaccine Approaches

Panelists

Michael Matthay, MD, UC San Francisco: ARDS Program

Rachael Callcut, MD, MSPH, FACS, UC Davis: ARDS Program 

John Zaia, MD, City of Hope: Convalescent Plasma Program 

Daniela Bota, MD, PhD, UC Irvine: Natural Killer Cells as a Treatment Strategy 

Key questions for panelists: 

  • Describe your trial or clinical program?
  • What steps did you take to provide access to disproportionately impacted communities?
  • How is it part of the overall scientific response to COVID-19? 
  • How has the ASCC Network infrastructure accelerated this response? 

Brief Break

Roundtable 2: Moderator Ysabel Duron, The Latino Cancer Institute and Latinas Contra Cancer

View Recording: Roundtable 2

Community Engagement and Lessons Learned from the COVID Programs.  

Panelists

Marsha Treadwell, PhD, UC San Francisco: Community Engagement  

Sheila Young, MD, Charles R. Drew University of Medicine and Science: Convalescent Plasma Program in the community

David Lo, MD, PhD,  UC Riverside: Bringing a public health perspective to clinical interventions

Key questions for panelists: 

  • What were important lessons learned from the COVID programs? 
  • How can CIRM and the ASCC Network achieve equipoise among communities and engender trust in clinical research? 
  • How can CIRM and the ASCC Network address structural barriers (e.g. job constrains, geographic access) that limit opportunities to participate in clinical trials?

Exploring tough questions, looking for answers

COVID-19 and social and racial injustice are two of the biggest challenges facing the US right now. This Thursday, October 8th, we are holding a conversation that explores finding answers to both.

The CIRM Alpha Stem Cell Clinic Network Symposium is going to feature presentations about advances in stem cell and regenerative research, highlighting treatments that are already in the clinic and being offered to patients.

But we’re also going to dive a little deeper into the work we support, and use it to discuss two of the most pressing issues of the day.

One of the topics being featured is research into COVID-19. To date CIRM has funded 17 different projects, including three clinical trials. We’ll talk about how these are trying to find ways to help people infected with the virus, seeing if stem cells can help restore function to organs and tissues damaged by the virus, and if we can use stem cells to help develop safe and effective vaccines.

Immediately after that we are going to use COVID-19 as a way of exploring how the people most at risk of being infected and suffering serious consequences, are also the ones most likely to be left out of the research and have most trouble accessing treatments and vaccines.

Study after study highlights how racial and ethnic minorities are underrepresented in clinical trials and disproportionately affected by debilitating diseases. We have a responsibility to change that, to ensure that the underserved are given the same opportunity to take part in clinical trials as other communities.

How do we do that, how do we change a system that has resisted change for so long, how do we overcome the mistrust that has built up in underserved communities following decades of abuse? We’ll be talking about with experts who are on the front lines of this movement.

It promises to be a lively meeting. We’d love to see you there. It’s virtual – of course – it’s open to everyone, and it’s free.

Here’s where you can register and find out more about the Symposium

Meet the people who are changing the future

Kristin MacDonald

Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.

I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.

Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.

That’s when you know the treatment works. At least for Rosie.

There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.

It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.

Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.

And it’s free!

You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.

We hope to see you there.

Perseverance: from theory to therapy. Our story over the last year – and a half

Some of the stars of our Annual Report

It’s been a long time coming. Eighteen months to be precise. Which is a peculiarly long time for an Annual Report. The world is certainly a very different place today than when we started, and yet our core mission hasn’t changed at all, except to spring into action to make our own contribution to fighting the coronavirus.

This latest CIRM Annual Reportcovers 2019 through June 30, 2020. Why? Well, as you probably know we are running out of money and could be funding our last new awards by the end of this year. So, we wanted to produce as complete a picture of our achievements as we could – keeping in mind that we might not be around to produce a report next year.

Dr. Catriona Jamieson, UC San Diego physician and researcher

It’s a pretty jam-packed report. It covers everything from the 14 new clinical trials we have funded this year, including three specifically focused on COVID-19. It looks at the extraordinary researchers that we fund and the progress they have made, and the billions of additional dollars our funding has helped leverage for California. But at the heart of it, and at the heart of everything we do, are the patients. They’re the reason we are here. They are the reason we do what we do.

Byron Jenkins, former Naval fighter pilot who battled back from his own fight with multiple myeloma

There are stories of people like Byron Jenkins who almost died from multiple myeloma but is now back leading a full, active life with his family thanks to a CIRM-funded therapy with Poseida. There is Jordan Janz, a young man who once depended on taking 56 pills a day to keep his rare disease, cystinosis, under control but is now hoping a stem cell therapy developed by Dr. Stephanie Cherqui and her team at UC San Diego will make that something of the past.

Jordan Janz and Dr. Stephanie Cherqui

These individuals are remarkable on so many levels, not the least because they were willing to be among the first people ever to try these therapies. They are pioneers in every sense of the word.

Sneha Santosh, former CIRM Bridges student and now a researcher with Novo Nordisk

There is a lot of information in the report, charting the work we have done over the last 18 months. But it’s also a celebration of everyone who made it possible, and our way of saying thank you to the people of California who gave us this incredible honor and opportunity to do this work.

We hope you enjoy it.

Helping the blind see – mice that is

When I first saw the headline for this story I thought of the nursery rhyme about the three blind mice. Finally, they’ll be able to see the farmer’s wife coming at them with a carving knife. But the real-world implications are of this are actually pretty exciting.

Researchers at the National Institute of Health’s National Eye Institute took skin cells from mice and directly reprogrammed them into becoming light sensitizing cells in the eye, the kind that are often damaged and destroyed by diseases like macular degeneration or retinitis pigmentosa.

What’s particularly interesting about this is that it bypassed the induced pluripotent stem cell (iPSC) stage where researchers turn the skin cells into embryonic-like cells, then turn those into the cells found in the eye.

In a news release, Anand Swaroop of the NEI says this more direct approach has a number of advantages: “This is the first study to show that direct, chemical reprogramming can produce retinal-like cells, which gives us a new and faster strategy for developing therapies for age-related macular degeneration and other retinal disorders caused by the loss of photoreceptors.”

After converting the skin cells into cells called rod photoreceptors – the light sensing cells found in the back of the eye – the team transplanted them into blind mice. One month later they tested the mice to see if there had been any change in vision. There had; 43 percent of the mice reacted to light exposure, something they hadn’t done before.

Biraj Mahato, the study’s first author, said that three months later, the transplanted cells were still alive and functioning. “Even mice with severely advanced retinal degeneration, with little chance of having living photoreceptors remaining, responded to transplantation. Such findings suggest that the observed improvements were due to the lab-made photoreceptors rather than to an ancillary effect that supported the health of the host’s existing photoreceptors.”

Obviously there is a lot of work still to do before we can even begin to think about trying something like this in people. But this is certainly an encouraging start.

In the meantime, CIRM is funding a number of stem cell programs aimed at treating vision destroying diseases like macular degeneration and retinitis pigmentosa.

You can bank on CIRM

Way back in 2013, the CIRM Board invested $32 million in a project to create an iPSC Bank. The goal was simple;  to collect tissue samples from people who have different diseases, turn those samples into high quality stem cell lines – the kind known as induced pluripotent stem cells (iPSC) – and create a facility where those lines can be stored and distributed to researchers who need them.

Fast forward almost seven years and that idea has now become the largest public iPSC bank in the world. The story of how that happened is the subject of a great article (by CIRM’s Dr. Stephen Lin) in the journal Science Direct.

Dr. Stephen Lin

In 2013 there was a real need for the bank. Scientists around the world were doing important research but many were creating the cells they used for that research in different ways. That made it hard to compare one study to another and come up with any kind of consistent finding. The iPSC Bank was designed to change that by creating one source for high quality cells, collected, processed and stored under a single, consistent method.

Tissue samples – either blood or skin – were collected from thousands of individuals around California. Each donor underwent a thorough consent process – including being shown a detailed brochure – to explain what iPS cells are and how the research would be done.

The diseases to be studied through this bank include:

  • Age-Related Macular Degeneration (AMD)
  • Alzheimer’s disease
  • Autism Spectrum Disorder (ASD)
  • Cardiomyopathies (heart conditions)
  • Cerebral Palsy
  • Diabetic Retinopathy
  • Epilepsy
  • Fatty Liver diseases
  • Hepatitis C (HCV)
  • Intellectual Disabilities
  • Primary Open Angle Glaucoma
  • Pulmonary Fibrosis

The samples were screened to make sure they were safe – for example the blood was tested for HBV and HIV – and then underwent rigorous quality control testing to make sure they met the highest standards.

Once approved the samples were then turned into iPSCs at a special facility at the Buck Institute in Novato and those lines were then made available to researchers around the world, both for-profit and non-profit entities.

Scientists are now able to use these cells for a wide variety of uses including disease modeling, drug discovery, drug development, and transplant studies in animal research models. It gives them a greater ability to study how a disease develops and progresses and to help discover and test new drugs or other therapies

The Bank, which is now run by FUJIFILM Cellular Dynamics, has become a powerful resource for studying genetic variation between individuals, helping scientists understand how disease and treatment vary in a diverse population. Both CIRM and Fuji Film are committed to making even more improvements and additions to the collection in the future to ensure this is a vital resource for researchers for years to come.