A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Charting a course for the future

A new home for stem cell research?

Have you ever been at a party where someone says “hey, I’ve got a good idea” and then before you know it everyone in the room is adding to it with ideas and suggestions of their own and suddenly you find yourself with 27 pages of notes, all of them really great ideas. No, me neither. At least, not until yesterday when we held the first meeting of our Scientific Strategy Advisory Panel.

This is a group that was set up as part of Proposition 14, the ballot initiative that refunded CIRM last November (thanks again everyone who voted for that). The idea was to create a panel of world class scientists and regulatory experts to help guide and advise our Board on how to advance our mission. It’s a pretty impressive group too. You can see who is on the SSAP here.  

The meeting involved some CIRM grantees talking a little about their work but mostly highlighting problems or obstacles they considered key issues for the future of the field as a whole. And that’s where the ideas and suggestions really started flowing hard and fast.

It started out innocently enough with Dr. Amander Clark of UCLA talking about some of the needs for Discovery or basic research. She advocated for a consortium approach (this quickly became a theme for many other experts) with researchers collaborating and sharing data and findings to help move the field along.

She also called for greater diversity in research, including collecting diverse cell samples at the basic research level, so that if a program advanced to later stages the findings would be relevant to a wide cross section of society rather than just a narrow group.

Dr. Clark also said that as well as supporting research into neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there needed to be a greater emphasis on neurological conditions such as autism, bipolar disorder and other mental health problems.

(CIRM is already committed to both increasing diversity at all levels of research and expanding mental health research so this was welcome confirmation we are on the right track).

Dr. Mike McCun called for CIRM to take a leadership role in funding fetal tissue research, things the federal government can’t or won’t support, saying this could really help in developing an understanding of prenatal diseases.

Dr. Christine Mummery, President of ISSCR, advocated for support for early embryo research to deepen our understanding of early human development and also help with issues of infertility.

Then the ideas started coming really fast:

  • There’s a need for knowledge networks to share information in real-time not months later after results are published.
  • We need standardization across the field to make it easier to compare study results.
  • We need automation to reduce inconsistency in things like feeding and growing cells, manufacturing cells etc.
  • Equitable access to CRISPR gene-editing treatments, particularly for underserved communities and for rare diseases where big pharmaceutical companies are less likely to invest the money needed to develop a treatment.
  • Do a better job of developing combination therapies – involving stem cells and more traditional medications.

One idea that seemed to generate a lot of enthusiasm – perhaps as much due to the name that Patrik Brundin of the Van Andel Institute gave it – was the creation of a CIRM Hotel California, a place where researchers could go to learn new techniques, to share ideas, to collaborate and maybe take a nice cold drink by the pool (OK, I just made that last bit up to see if you were paying attention).

The meeting was remarkable not just for the flood of ideas, but also for its sense of collegiality.  Peter Marks, the director of the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA-CBER) captured that sense perfectly when he said the point of everyone working together, collaborating, sharing information and data, is to get these projects over the finish line. The more we work together, the more we will succeed.

You can’t take it if you don’t make it

Biomedical specialist Mamadou Dialio at work in the Cedars-Sinai Biomanufacturing Center. Photo by Cedars-Sinai.

Following the race to develop a vaccine for COVID-19 has been a crash course in learning how complicated creating a new therapy is. It’s not just the science involved, but the logistics. Coming up with a vaccine that is both safe and effective is difficult enough, but then how do you make enough doses of it to treat hundreds of millions of people around the world?

That’s a familiar problem for stem cell researchers. As they develop their products they are often able to make enough cells in their own labs. But as they move into clinical trials where they are testing those cells in more and more people, they need to find a new way to make more cells. And, of course, they need to plan ahead, hoping the therapy is approved by the Food and Drug Administration, so they will need to be able to manufacture enough doses to meet the increased demand.

We saw proof of that planning ahead this week with the news that Cedars-Sinai Medical Center in Los Angeles has opened up a new Biomanufacturing Center.

Dr. Clive Svendsen, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, said in a news release, the Center will manufacture the next generation of drugs and regenerative medicine therapies.

“The Cedars-Sinai Biomanufacturing Center leverages our world-class stem-cell expertise, which already serves scores of clients, to provide a much-needed biomanufacturing facility in Southern California. It is revolutionary by virtue of elevating regenerative medicine and its therapeutic possibilities to an entirely new level-repairing the human body.”

This is no ordinary manufacturing plant. The Center features nine “clean rooms” that are kept free from dust and other contaminants. Everyone working there has to wear protective suits and masks to ensure they don’t bring anything into the clean rooms.

The Center will specialize in manufacturing induced pluripotent stem cells, or iPSCs. Dhruv Sareen, PhD, executive director of the Biolmanufacturing Center, says iPSCs are cells that can be turned into any other kind of cell in the body.

“IPSCs are powerful tools for understanding human disease and developing therapies. These cells enable us to truly practice precision medicine by developing drug treatments tailored to the individual patient or groups of patients with similar genetic profiles.”

The Biomanufacturing Center is designed to address a critical bottleneck in bringing cell- and gene-based therapies to the clinic. After all, developing a therapy is great, but it’s only half the job. Making enough of it to help the people who need it is the other half.

CIRM is funding Dr. Svendsen’s work in developing therapies for ALS and other diseases and disorders.  

A guide to healing

Dr. Evan Snyder

Having grown up in an era where to find your way around you had to use paper maps, a compass and a knowledge of the stars (OK, I’m not actually that old!) I’m forever grateful to whoever invented the GPS. It’s a lifesaver, and I daresay has also saved more than a few marriages!

Having a way to guide people where they need to be is amazing. Now researchers at Sanford Burnham Prebys Medical Discovery Institute have come up with a similar tool for stem cells. It’s a drug that can help guide stem cells to go where they need to go, to repair damaged tissue and improve the healing process.

In a news release Evan Snyder, MD, PhD, the senior author of the study, explained in wonderfully simply terms what they have done:

“The ability to instruct a stem cell where to go in the body or to a particular region of a given organ is the Holy Grail for regenerative medicine. Now, for the first time ever, we can direct a stem cell to a desired location and focus its therapeutic impact.”

More than a decade ago Snyder and his team discovered that when our body suffers an injury the result is often inflammation and that this then sends out signals for stem cells to come and help repair the damage. This is fine when the problem is a cut or sprain, short term issues in need of a quick fix. But what happens if it’s something more complex, such as a heart attack or stroke where the need is more long term.

In the study, funded in part by CIRM, the team took a molecule, called CXCL12, known to help guide stem cells to damaged tissue, and used it to create a drug called SDV1a. Snyder says this new drug has several key properties.

“Since inflammation can be dangerous, we modified CXCL12 by stripping away the risky bit and maximizing the good bit. Now we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation.”

To test the drug to see how well it worked the team implanted SDV1a and some human brain stem cells into mice with Sandhoff disease, a condition that progressively destroys cells in the brain and spinal cord. They were able to demonstrate that the drug helped the stem cells migrate to where they were needed and to help in repairing the damage. The treated mice had a longer lifespan and better motor function, as well as developing symptoms later than untreated mice.

The team is now testing this drug to see if it has any impact on ALS, also known as Lou Gehrig’s disease. And Snyder says there are other areas where it could prove effective.

“We are optimistic that this drug’s mechanism of action may potentially benefit a variety of neurodegenerative disorders, as well as non-neurological conditions such as heart disease, arthritis and even brain cancer. Interestingly, because CXCL12 and its receptor are implicated in the cytokine storm that characterizes severe COVID-19, some of our insights into how to selectively inhibit inflammation without suppressing other normal processes may be useful in that arena as well.”

CIRM’s President & CEO, Dr. Maria Millan, says this kind of work highlights the important role the stem cell agency plays, in providing long-term support for promising but early stage research.

“Thanks to decades of investment in stem cell science, we are making tremendous progress in our understanding of how these cells work and how they can be harnessed to help reverse injury or disease. Dr. Snyder’s group has identified a drug that could boost the ability of neural stem cells to home to sites of injury and initiate repair. This candidate could help speed the development of stem cell treatments for conditions such as spinal cord injury and Alzheimer’s disease.”

The discovery is published in the Proceedings of the National Academy of Sciences (PNAS)

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.

A true Hall of Fame winner

Dr. Larry Goldstein: Photo courtesy UCSD

You know you are working with some of the finest scientific minds in the world when they get elected to the prestigious National Academy of Sciences (NAS). It’s the science equivalent of the baseball, football or even Rock and Roll Hall of Fame. People only get in if their peers vote them in. It’s considered one of the highest honors in science, one earned over many decades of hard work. And when it comes to hard work there are few people who work harder than U.C. San Diego’s Dr. Lawrence Goldstein, one of the newly elected members of the NAS.

Dr. Goldstein – everyone calls him Larry – was the founder and director of the UCSD Stem Cell Program and the Sanford Stem Cell Clinical Center at UC San Diego Health and is founding scientific director of the Sanford Consortium for Regenerative Medicine.

For more than 25 years Larry’s work has targeted the brain and, in particular, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) better known as Lou Gehrig’s disease.

In 2012 his team was the first to create stem cell models for two different forms of Alzheimer’s, the hereditary and the sporadic forms. This gave researchers a new way of studying the disease, helping them better understand what causes it and looking at new ways of treating it.

His work has also helped develop a deeper understanding of the genetics of Alzheimer’s and to identify possible new targets for stem cell and other therapies.

Larry was typically modest when he heard the news, saying: “I have been very fortunate to have wonderful graduate students and fellows who have accomplished a great deal of excellent research. It is a great honor for me and for all of my past students and fellows – I am obviously delighted and hope to contribute to the important work of the National Academy of Sciences.”

But Larry doesn’t intend to rest on his laurels. He says he still has a lot of work to do, including “raising funding to test a new drug approach for Alzheimer’s disease that we’ve developed with CIRM support.”

Jennifer Briggs Braswell, PhD, worked with Larry at UCSD from 2005 to 2018. She says Larry’s election to the NAS is well deserved:

“His high quality publications, the pertinence of his studies in neurodegeneration to our current problems, and his constant, unwavering devotion to the next generation of scientists is matched only by his dedication to improving public understanding of science to motivate social, political, and financial support.  

“He has been for me a supportive mentor, expressing enthusiastic belief in the likely success of my good ideas and delivering critique with kindness and sympathy.   He continues to inspire me, our colleagues at UCSD and other communities, advocate publicly for the importance of science, and work tirelessly on solutions for neurodegenerative disorders.”

You can read about Larry’s CIRM-supported work here.

You can watch an interview with did with Larry a few years ago.

CIRM Board Meeting Highlights Important Updates to Clinical Trials

Dr. Maria T. Millan, President and CEO of CIRM, presenting the President’s Report

This past Thursday the governing Board of the California Institute for Regenerative Medicine (CIRM) were presented with an update on CIRM’s clinical portfolio, which to date includes 60 clinical trials in various areas including kidney failure, cancer, and other rare diseases.  The full President’s Report gives an update on 15 of these trials, in addition to our landmark Cure Sickle Cell Initiative with the NIH and our various educational programs.

Although we won’t be diving into extensive detail for all of these trials, we wanted to highlight several key updates made in this presentation to demonstrate how our clinical portfolio is maturing, with many of these trials moving towards registration. Classically, registration trials are large Phase 3 trials. Notably, some of the highlighted CIRM trials are small Phase 2 or earlier trials that seek to gain enough safety and efficacy data to support final FDA marketing approval. This is a trend with regenerative medicine programs where trial sizes are often small due to the fact that the affected populations are so small with some of these rare diseases. Despite this, the approaches could allow a so called “large effect size,” meaning the signal of clinical benefit per patient is strong enough to give a read of whether the therapy is working or not. CIRM programs often address rare unmet needs and utilize this approach.

For example, Orchard Therapeutics, which is conducting a phase 2 clinical trial for ADA Severe Combined Immunodeficiency (ADA-SCID), a rare immune disorder caused by a genetic mutation, has shown a long-term recovery of the immune system in 20 patients two years post treatment.  Orchard plans to submit a Biologics License Application (BLA) sometime in 2020, which is the key step necessary to obtain final approval from the Food and Drug Administration (FDA) for a therapy.

“We are thrilled to see encouraging results for this genetically modified cell therapy approach and a path forward for FDA approval,” says Maria T. Millan, MD, President and CEO of CIRM. “CIRM is proud of the role it has played in this program.  We funded the program while it was at UCLA and it is now in partnership with Orchard Therapeutics as it takes the program through this final phase toward FDA marketing approval.  Success in this program is a game changer for patients with ADA-SCID who had no other options and who had no bone marrow transplant donors. It also opens up possibilities for future approaches for this dieaseas as well as the other 6,000 genetic diseases that currently have no treatment.”    

The trial uses a gene therapy approach that takes the patient’s own blood stem cells, introduces a functional version of the ADA gene, and reintroduces these corrected blood stem cells back into the patient. From blood tests, one can readily detect whether the approach is successful from the presence of ADA and from the presence of immune cells that were not previously present. To date, it has been awarded approximately $19 million in CIRM funding.  Additionally, it has received FDA Breakthrough Therapy as well as Orphan Drug Designations, both of which are designed to accelerate  the development of the treatment.

Another trial that was highlighted is Rocket Pharmaceutical’s clinical trial for Leukocyte Adhesion Deficiency-1 (LAD-1), a rare and fatal pediatric disease that affects the body’s ability to combat infections. They have just released initial results from their first patient. This is also a gene therapy approach using the patient’s own blood stem cells. The notable aspect of this trial is that the investigators designed this small phase 1 trial of nine patients to be “registration enabling.”  This means that, if they find compelling data, they intend to bring the experience and data from this trial to the FDA to seek agreement on what would be required to get final marketing approval in order to get this treatment to patients with severe unmet medical needs in the most timely way possible.     

Preliminary results demonstrate early evidence of safety and potential efficacy.  There were visible improvements in multiple disease-related skin lesions after receiving the therapy. They are collecting more data on more patients.  To date, it has received $6.6 million in CIRM funding.

As a unique immuno-oncology approach (using the body’s immune system to battle cancer), CIRM is funding Forty Seven Inc. to conduct a clinical trial for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), both of which are forms of cancer.  They have received Fast Track and Orphan Drug designation from the FDA.

The trial is using an antibody blocking CD47, a “don’t eat me” signal, which allows the body’s own immune cells to seek and destroy cancerous stem cells.  This is combined with chemotherapy to render the cancer stem cells more susceptible to immune destruction.  This trial has received $5 million in CIRM funding thus far.

Other registration phase trials in the CIRM portfolio include the following Phase 3 trials:

Brainstorm Cell Therapeutics, for a fatal debilitating neurodegenerative disease, Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease).  That company has completed enrollment and expects top line results in the final quarter of 2020.

Humacyte, which is testing bioengineered de-cellularized vessels that are implanted to create vascular access that is repopulated by the patients own stem cells to make it more like native vessel.  The company is conducting two Phase 3 trials to compare this bioengineered vessel to synthetic grafts and to the patients’ own vessels for use in hemodialysis, a “life line” for patients with end stage renal disease. Humacyte was the first US FDA Cell Therapy program to receive the Regenerative Medicine Advanced Technologies (RMAT) in March 2017. To date, these trials have been awarded $24 million in CIRM funding.

Medeor Therapeutics has received $11.2M in CIRM funding to conduct a Phase 3 trial in combined blood stem cell and kidney transplantation to induce immunologic tolerance so that the blood stem cells teach the patient’s immune system to recognize the transplanted kidney as its own.  The goal is to remove the need for chronic immunosuppressive medications, that have its own complications. If successful, transplant recipients would not need to “trade one chronic condition for another.”

CIRM supported study of gene silencer blocks ALS degeneration, saves motor function

Dr. Martin Marsala, UC San Diego

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that destroys the nerve cells in the brain and spinal cord. As a result of ALS, the motor neurons that enable bodily movement and muscle control are harmed, which can make it difficult to move, speak, eat, and breathe. This condition usually affects people from age 40 to 70, but individuals in their 20s and 30s have also been known to develop ALS. Unfortunately there is no cure for this condition.

However, a study supported by CIRM and conducted by Dr. Martin Marsala at UC San Diego is using a mouse model to look at an approach that uses a gene silencer to protect motor neurons before or shortly after ALS symptoms start to develop.

The gene silencer works by turning off a targeted gene and is delivered via injection. In the case of ALS, previous research suggests that mutations in a gene called SOD1 may cause motor neuronal cell death, resulting in ALS. For this study, Dr. Marsala and his team injected the gene silencer at two sites in the spinal cord in adult mice expressing an ALS-causing mutation of the SOD1 gene. The mice injected did not yet display symptoms of ALS or had only begun showing symptoms.

In mice not yet showing ALS symptoms, they displayed normal neurological function with no onset ALS symptoms after treatment. Additionally, near complete protection of motor neurons and other cells was observed. In mice that had just began showing ALS symptoms, the injection blocked further disease progression as well as further harm to remaining motor neurons. Both of these groups of mice lived without negative side effects for the duration of the study.

In a news release, Dr. Marsala talks about what these results mean for the study of ALS.

“At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS.”

The next steps for this research would be to conduct additional safety studies with a larger animal model in order to determine an optimal, safe dose for the treatment.

The full results of this study were published in Nature Medicine.

In addition to supporting this research for ALS, CIRM has funded two clinical trials in the field as well. One of these trials is being conducted by BrainStorm Cell Therapeutics and the other trial is being by Cedars-Sinai Medical Center.