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)

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?

Charting a new course for stem cell research

What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.

Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.

The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?

It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.

We’ll hear what’s being done to find therapies for

  • Rare diseases that affect children
  • Type 1 diabetes
  • HIV/AIDS
  • Glioblastoma
  • Multiple myeloma

We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.

It’s going to be a fascinating day. And did I mention it’s free!

All you have to do is go to this Eventbrite page to register.

And feel free to share this with your family, friends or anyone you think might be interested.

We look forward to seeing you there.

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 new voice and vision added to CIRM Board

UC Davis School of Medicine Dean, Dr. Allison Brashear: Photo courtesy UCD

We have a new member on the CIRM Board – Dr. Allison Brashear is the Dean of the UC Davis School of Medicine, overseeing one of the nation’s top research, academic and medical training institutions.

Dr. Brashear is an internationally known researcher in movement disorders and an expert in ATP1A3-related diseases, a spectrum of rare neurologic disorders.

Before joining UC Davis, Dr. Brashear was professor and chair of the Department of Neurology for 14 years at Wake Forest School of Medicine.

She serves on the American Board of Psychiatry and Neurology, and has served on the boards of the American Neurological Association and the American Academy of Neurology, where she was instrumental in crafting a leadership program for women, now expanded to include leadership development for minorities.

You can read more about her background in this news release. But we wanted to get a sense of what motivates and inspires Dr. Brashear. So we asked her. And she told us.

Dean Brashear being sworn in – virtually – on the CIRM Board. Top left, James Harrision CIRM General Counsel; Jonathan Thomas, CIRM Board Chair; Dr. Brashear; and Dr. Jim Kovach, Director of Industry Alliances at UC Davis, alternative Board member.

When did you get interested in science? Was this always something you knew you wanted to do?

I loved math and science in middle school and continued with science in college. I grew up hearing my parents talk about caring for patients and the impact you could have on them and their family’s lives. My father is a pulmonologist and my mother was a Ph.D. in marriage and family therapy. Together they taught me the value of patient-centered care. 

My mother was a tremendous advocate for women. When I was in middle school she took my friend and I to the state legislature and we watched the ERA (Equal Rights Amendment) debates. It’s a powerful memory but not always flattering about what people thought at the time. So, from an early age I really became a strong advocate for women, to make sure women had opportunities and that we were an inclusive culture wherever I was. 

As a woman going into a male dominated field, how did you manage to push past the skeptics and doubters to succeed? 

Early on I recognized the need to work with senior faculty who would give me an opportunity to lead and learn.  I became a chair of neurology at Wake Forest when I was 44 and was the only woman chair for 4 years. When I was appointed to the Wake Forest Baptist Medical Center Board of Directors as one of two faculty, I was the only woman. I learned early on that it was important to have sponsorship from senior leaders to succeed. I learned that, when opportunities presented themselves, to say “yes.” This is how I became the lead investigator into ATP1A3 related diseases in 1991. That project, now 11 years funded by the NIH, is one that is led by me and three other women. 

It’s still not uncommon for me to walk into a room and be the only woman. And so, making sure that there is appropriate support for women leaders is really key.

Did you have mentors to help you along the way – what was their advice to you?

I prefer the term sponsorship. Mentors advise – which is important, but more important is the role of the sponsor. A sponsor goes out of their way to advance another career. This can be a public call-out, a well-placed phone call or giving a resident what ends up being a new pathway of research.  I appreciate the many sponsors in my life, and that includes men and women.  I aspire to be a similar sponsor. This is my way to pay it forward. 

How do you sponsor others to help them overcome barriers, etc.? 

I advise women to get extra leadership training, learn about money and to make sure to have a network of advocates. I also remind them to say thank you to those who pave the way. 

I think it goes down to the message that you meet these key people in your life and they go the extra mile to help you and you, as a leader, need to take that opportunity and really just launch from it. Along the way I found I really wanted to bring people in and grow them and that was the best part of being chair of the department and one of the reasons I wanted to be a dean. When faculty join our health system I want to set them up to succeed. Celebrating others’ success with them is a great feeling. Fostering these successes is how we can be a catalyst to research and care innovations that improve health, which is at the heart of our work.  

These are interesting times to head a major university, what advice and encouragement do you have for students just starting out who face their first year “at university” at home? 

Every change brings opportunity. University at home is hard – interpersonal relationships are so important to learning and we miss that when we are on Zoom. I advise students and faculty to nurture those social connections.

When you are not working what do you do for fun?  

I hang out with my husband and our two rescue dogs. We are making plans to go explore California when the COVID-19 pandemic settles down. We had our two adult children home during the shutdown, but both are back at school on the East Coast. 

Parkinson’s Disease and Stem Cells

Lila Collins, PhD

A few weeks ago we held a Facebook Live “Ask the Stem Cell Team About Parkinson’s Disease” event. As you can imagine we got lots of questions but, because of time constraints, only had time to answer a few. Thanks to my fabulous CIRM colleagues, Dr. Lila Collins and Dr. Kent Fitzgerald, for putting together answers to some of the other questions. Here they are.

Kent Fitzgerald, PhD

Q: It seems like we have been hearing for years that stem cells can help people with Parkinson’s, why is it taking so long?

A: Early experiments in Sweden using fetal tissue did provide a proof of concept for the strategy of replacing dopamine producing cells damaged or lost in Parkinson’s disease (PD) . At first, this seemed like we were on the cusp of a cell therapy cure for PD, however, we soon learned based on some side effects seen with this approach (in particular dyskinesias or uncontrollable muscle movements) that the solution was not as simple as once thought. 

While this didn’t produce the answer it did provide some valuable lessons.

The importance of dopaminergic (DA) producing cell type and the location in the brain of the transplant.  Simply placing the replacement cells in the brain is not enough. It was initially thought that the best site to place these DA cells is a region in the brain called the SN, because this area helps to regulate movement. However, this area also plays a role in learning, emotion and the brains reward system. This is effectively a complex wiring system that exists in a balance, “rewiring” it wrong can have unintended and significant side effects. 

Another factor impacting progress has been understanding the importance of disease stage. If the disease is too advanced when cells are given then the transplant may no longer be able to provide benefit.  This is because DA transplants replace the lost neurons we use to control movement, but other connected brain systems have atrophied in response to losing input from the lost neurons. There is a massive amount of work (involving large groups and including foundations like the Michael J Fox Foundation) seeking to identify PD early in the disease course where therapies have the best chance of showing an effect.   Clinical trials will ultimately help to determine the best timing for treatment intervention.

Ideally, in addition to the cell therapies that would replace lost or damaged cells we also want to find a therapy that slows or stops the underlying biology causing progression of the disease.

So, I think we’re going to see more gene therapy trials including those targeting the small minority of PD that is driven by known mutations.  In fact, Prevail Therapeutics will soon start a trial in patients with GBA1 mutations. Hopefully, replacing the enzyme in this type of genetic PD will prevent degeneration.

And, we are also seeing gene therapy approaches to address forms of PD that we don’t know the cause, including a trial to rescue sick neurons with GDNF which is a neurotrophic factor (which helps support the growth and survival of these brain cells) led by Dr Bankiewicz  and trials by Axovant and Voyager, partnered with Neurocrine aimed at restoring dopamine generation in the brain.

 A small news report came out earlier this year about a recently completed clinical trial by Roche Pharma and Prothena. This addressed the build up in the brain of what are called lewy bodies, a problem common to many forms of PD. While the official trial results aren’t published yet, a recent press release suggests reason for optimism.  Apparently, the treatment failed to statistically improve the main clinical measurement, but other measured endpoints saw improvement and it’s possible an updated form of this treatment will be tested again in the hopes of seeing an improved effect.

Finally, I’d like to call attention to the G force trials. Gforce is a global collaborative effort to drive the field forward combining lessons learned from previous studies with best practices for cell replacement in PD.  These first-in-human safety trials to replace the dopaminergic neurons (DANs) damaged by PD have shared design features including identifying what the best goals are and how to measure those.

The CIRA trial, Dr Jun Takahashi

The NYSTEM PD trial, Dr Lorenz Studer

The EUROSTEMPD trial, Dr Roger Barker.

And the Summit PD trial, Dr Jeanne Loring of Aspen Neuroscience.

Taken together these should tell us quite a lot about the best way to replace these critical neurons in PD.

As with any completely novel approach in medicine, much validation and safety work must be completed before becoming available to patients

The current approach (for cell replacement) has evolved significantly from those early studies to use cells engineered in the lab to be much more specialized and representing the types believed to have the best therapeutic effects with low probability of the side effects (dyskinesias) seen in earlier trials. 

If we don’t really know the cause of Parkinson’s disease, how can we cure it or develop treatments to slow it down?

PD can now be divided into major categories including 1. Sporadic, 2. Familial. 

For the sporadic cases, there are some hallmarks in the biology of the neurons affected in the disease that are common among patients.  These can be things like oxidative stress (which damages cells), or clumps of proteins (like a-synuclein) that serve to block normal cell function and become toxic, killing the DA neurons. 

The second class of “familial” cases all share one or more genetic changes that are believed to cause the disease.  Mutations in genes (like GBA, LRRK2, PRKN, SNCA) make up around fifteen percent of the population affected, but the similarity in these gene mutations make them attractive targets for drug development.

CIRM has funded projects to generate “disease in a dish” models using neurons made from adults with Parkinson’s disease.   Stem cell-derived models like this have enabled not only a deep probing of the underlying biology in Parkinson’s, which has helped to identify new targets for investigation, but have also allowed for the testing of possible therapies in these cell-based systems. 

iPSC-derived neurons are believed to be an excellent model for this type of work as they can possess known familial mutations but also show the rest of the patients genetic background which may also be a contributing factor to the development of PD. They therefore contain both known and unknown factors that can be tested for effective therapy development.

I have heard of scientists creating things called brain organoids, clumps of brain cells that can act a little bit like a brain. Can we use these to figure out what’s happening in the brain of people with Parkinson’s and to develop treatments?

There is considerable excitement about the use of brain organoids as a way of creating a model for the complex cell-to-cell interactions in the brain.  Using these 3D organoid models may allow us to gain a better understanding of what happens inside the brain, and develop ways to treat issues like PD.

The organoids can contain multiple cell types including microglia which have been a hot topic of research in PD as they are responsible for cleaning up and maintaining the health of cells in the brain.  CIRM has funded the Salk Institute’s Dr. Fred Gage’s to do work in this area.

If you go online you can find lots of stem cells clinics, all over the US, that claim they can use stem cells to help people with Parkinson’s. Should I go to them?

In a word, no! These clinics offer a wide variety of therapies using different kinds of cells or tissues (including the patient’s own blood or fat cells) but they have one thing in common; none of these therapies have been tested in a clinical trial to show they are even safe, let alone effective. These clinics also charge thousands, sometimes tens of thousands of dollars these therapies, and because it’s not covered by insurance this all comes out of the patient’s pocket.

These predatory clinics are peddling hope, but are unable to back it up with any proof it will work. They frequently have slick, well-designed websites, and “testimonials” from satisfied customers. But if they really had a treatment for Parkinson’s they wouldn’t be running clinics out of shopping malls they’d be operating huge medical centers because the worldwide need for an effective therapy is so great.

Here’s a link to the page on our website that can help you decide if a clinical trial or “therapy” is right for you.

Is it better to use your own cells turned into brain cells, or cells from a healthy donor?

This is the BIG question that nobody has evidence to provide an answer to. At least not yet.

Let’s start with the basics. Why would you want to use your own cells? The main answer is the immune system.  Transplanted cells can really be viewed as similar to an organ (kidney, liver etc) transplant. As you likely know, when a patient receives an organ transplant the patient’s immune system will often recognize the tissue/organ as foreign and attack it. This can result in the body rejecting what is supposed to be a life-saving organ. This is why people receiving organ transplants are typically placed on immunosuppressive “anti-rejection “drugs to help stop this reaction. 

In the case of transplanted dopamine producing neurons from a donor other than the patient, it’s likely that the immune system would eliminate these cells after a short while and this would stop any therapeutic benefit from the cells.  A caveat to this is that the brain is a “somewhat” immune privileged organ which means that normal immune surveillance and rejection doesn’t always work the same way with the brain.  In fact analysis of the brains collected from the first Swedish patients to receive fetal transplants showed (among other things) that several patients still had viable transplanted cells (persistence) in their brains.

Transplanting DA neurons made from the patient themselves (the iPSC method) would effectively remove this risk of the immune system attack as the cells would not be recognized as foreign.

CIRM previously funded a discovery project with Jeanne Loring from Scripps Research Institute that sought to generate DA neurons from Parkinson’s patients for use as a potential transplant therapy in these same patients.   This project has since been taken on by a company formed, by Dr Loring, called Aspen Neuroscience.  They hope to bring this potential therapy into clinical trials in the near future.    

A commonly cited potential downside to this approach is that patients with genetic (familial) Parkinson’s would be receiving neurons generated with cells that may have the same mutations that caused the problem in the first place. However, as it can typically take decades to develop PD, these cells could likely function for a long time. and prove to be better than any current therapies.

Creating cells from each individual patient (called autologous) is likely to be very expensive and possibly even cost-prohibitive. That is why many researchers are working on developing an “off the shelf” therapy, one that uses cells from a donor (called allogeneic)would be available as and when it’s needed.

When the coronavirus happened, it seemed as if overnight the FDA was approving clinical trials for treatments for the virus. Why can’t it work that fast for Parkinson’s disease?

While we don’t know what will ultimately work for COVID-19, we know what the enemy looks like.  We also have lots of experience treating viral infections and creating vaccines.  The coronavirus has already been sequenced, so we are building upon our understanding of other viruses to select a course to interrupt it.  In contrast, the field is still trying to understand the drivers of PD that would respond to therapeutic targeting and therefore, it’s not precisely clear how best to modify the course of neurodegenerative disease.  So, in one sense, while it’s not as fast as we’d like it to be, the work on COVID-19 has a bit of a head start.

Much of the early work on COVID-19 therapies is also centered on re-purposing therapies that were previously in development.  As a result, these potential treatments have a much easier time entering clinical trials as there is a lot known about them (such as how safe they are etc.).  That said, there are many additional therapeutic strategies (some of which CIRM is funding) which are still far off from being tested in the clinic. 

The concern of the Food and Drug Administration (FDA) is often centered on the safety of a proposed therapy.  The less known, the more cautious they tend to be. 

As you can imagine, transplanting cells into the brain of a PD patient creates a significant potential for problems and so the FDA needs to be cautious when approving clinical trials to ensure patient safety.

CIRM Board Approves Clinical Trials Targeting COVID-19 and Sickle Cell Disease

Coronavirus particles, illustration.

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved new clinical trials for COVID-19 and sickle cell disease (SCD) and two earlier stage projects to develop therapies for COVID-19.

Dr. Michael Mathay, of the University of California at San Francisco, was awarded $750,000 for a clinical trial testing the use of Mesenchymal Stromal Cells for respiratory failure from Acute Respiratory Distress Syndrome (ARDS). In ARDS, patients’ lungs fill up with fluid and are unable to supply their body with adequate amounts of oxygen. It is a life-threatening condition and a major cause of acute respiratory failure. This will be a double-blind, randomized, placebo-controlled trial with an emphasis on treating patients from under-served communities.

This award will allow Dr. Matthay to expand his current Phase 2 trial to additional underserved communities through the UC Davis site.

“Dr. Matthay indicated in his public comments that 12 patients with COVID-related ARDS have already been enrolled in San Francisco and this funding will allow him to enroll more patients suffering from COVID- associated severe lung injury,” says Dr. Maria T. Millan, CIRM’s President & CEO. “CIRM, in addition to the NIH and the Department of Defense, has supported Dr. Matthay’s work in ARDS and this additional funding will allow him to enroll more COVID-19 patients into this Phase 2 blinded randomized controlled trial and expand the trial to 120 patients.”

The Board also approved two early stage research projects targeting COVID-19.

  • Dr. Stuart Lipton at Scripps Research Institute was awarded $150,000 to develop a drug that is both anti-viral and protects the brain against coronavirus-related damage.
  • Justin Ichida at the University of Southern California was also awarded $150,00 to determine if a drug called a kinase inhibitor can protect stem cells in the lungs, which are selectively infected and killed by the novel coronavirus.

“COVID-19 attacks so many parts of the body, including the lungs and the brain, that it is important for us to develop approaches that help protect and repair these vital organs,” says Dr. Millan. “These teams are extremely experienced and highly renowned, and we are hopeful the work they do will provide answers that will help patients battling the virus.”

The Board also awarded Dr. Pierre Caudrelier from ExcellThera $2 million to conduct a clinical trial to treat sickle cell disease patients

SCD is an inherited blood disorder caused by a single gene mutation that results in the production of “sickle” shaped red blood cells. It affects an estimated 100,000 people, mostly African American, in the US and can lead to multiple organ damage as well as reduced quality of life and life expectancy.  Although blood stem cell transplantation can cure SCD fewer than 20% of patients have access to this option due to issues with donor matching and availability.

Dr. Caudrelier is using umbilical cord stem cells from healthy donors, which could help solve the issue of matching and availability. In order to generate enough blood stem cells for transplantation, Dr. Caudrelier will be using a small molecule to expand these blood stem cells. These cells would then be transplanted into twelve children and young adults with SCD and the treatment would be monitored for safety and to see if it is helping the patients.

“CIRM is committed to finding a cure for sickle cell disease, the most common inherited blood disorder in the U.S. that results in unpredictable pain crisis, end organ damage, shortened life expectancy and financial hardship for our often-underserved black community” says Dr. Millan. “That’s why we have committed tens of millions of dollars to fund scientifically sound, innovative approaches to treat sickle cell disease. We are pleased to be able to support this cell therapy program in addition to the gene therapy approaches we are supporting in partnership with the National Heart, Lung and Blood Institute of the NIH.”

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.

Ask the Stem Cell Team About Autism

On March 19th we held a special Facebook Live “Ask the Stem Cell Team About Autism” event. We were fortunate enough to have two great experts – Dr. Alysson Muotri from UC San Diego, and CIRM’s own Dr. Kelly Shepard. As always there is a lot of ground to cover in under one hour and there are inevitably questions we didn’t get a chance to respond to. So, Dr. Shepard has kindly agreed to provide answers to all the key questions we got on the day.

If you didn’t get a chance to see the event you can watch the video here. And feel free to share the link, and this blog, with anyone you think might be interested in the material.

Dr. Kelly Shepard

Can umbilical cord blood stem cells help reduce some of the symptoms?

This question was addressed by Dr. Muotri in the live presentation. To recap, a couple of clinical studies have been reported from scientists at Duke University and Sutter Health, but the results are not universally viewed as conclusive.  The Duke study, which focused on very young children, reported some improvements in behavior for some of the children after treatment, but it is important to note that this trial had no placebo control, so it is not clear that those patients would not have improved on their own. The Duke team has moved forward with larger trial and placebo control.

Does it have to be the child’s own cord blood or could donated blood work too?

In theory, a donated cord product could be used for similar purposes as a child’s own cord, but there is a caveat- the donated cord tissues must have some level of immune matching with the host in order to not be rejected or lead to other complications, which under certain circumstances, could be serious.

Some clinics claim that the use of fetal stem cells can help stimulate improved blood and oxygen flow to the brain. Could that help children with autism?

Fetal stem cells have been tested in FDA approved/sanctioned clinical trials for certain brain conditions such as stroke and Parkinson Disease, where there is clearer understanding of how and which parts of the brains are affected, which nerve cells have been lost or damaged, and where there is a compelling biological rationale for how certain properties the transplanted cells, such as their anti-inflammatory properties, could provide benefit.

Alysson Muotri in his lab and office at Sanford Consortium in La Jolla, California; Photograph by David Ahntholz http://www.twopointpictures.com http://www.davidahntholz.com

In his presentation, Dr. Muotri noted that neurons are not lost in autistic brains, so there is nothing that would be “replaced” by such a treatment. And although some forms of autism might include inflammation that could potentially be mitigated, it is unlikely that  the degree of benefit that might come from reducing inflammation would be worth the risks of the treatment, which includes intracranial injection of donated material.  Unfortunately, we still do not know enough about the specific causes and features of autism to determine if and to what extent stem cell treatments could prove helpful. But we are learning more every day, especially with some of the new technologies and discoveries that have been enabled by stem cell technology. 

Some therapies even use tissue from sheep claiming that a pill containing sheep pancreas can migrate to and cure a human pancreas, pills containing sheep brains can help heal human brains. What are your thoughts on those?

For some conditions, there may be a scientific rationale for how a specific drug or treatment could be delivered orally, but this really depends on the underlying biology of the condition, the means by which the drug exerts its effect, and how quickly that drug or substance will be digested, metabolized, or cleared from the body’s circulation. Many drugs that are delivered orally do not reach the brain because of the blood-brain barrier, which serves to isolate and protect the brain from potentially harmful substances in the blood circulation. For such a drug to be effective, it would have to be stable within the body for a period of time, and be something that could exert its effects on the brain either directly or indirectly.

Sheep brain or pancreas (or any other animal tissue consumed) in a pill form would be broken down into basic components immediately by digestion, i.e. amino acids, sugars, much like any other meat or food. Often complex treatments designed to be specifically targeted to the brain are delivered by intra-cranial/intrathecal injection, or by developing special strategies to evade the blood brain barrier, a challenge that is easier said than done. For autism, there is still a lot to be learned regarding how a therapeutic intervention might work to help people, so for now, I would caution against the use of dietary supplements or pills that are not prescribed or recommended by your doctor. 

What are the questions parents should ask before signing up for any stem cell therapy

There is some very good advice about this on the both the CIRM and ISSCR websites, including a handbook for patients that includes questions to ask anyone offering you a stem cell treatment, and also some fundamental facts that everyone should know about stem cells. https://www.closerlookatstemcells.org/patient-resources/

What kinds of techniques do we have now that we didn’t have in the past that can help us better understand what is happening in the brain of a child with autism.

We covered this in the online presentation. Some of the technologies discussed include:

– “disease in a dish” models from patient derived stem cells for studying causes of autism

–  new ways to make human neurons and other cell types for study

– organoid technology, to create more realistic brain tissues for studying autism

– advances in genomics and sequencing technologies to identify “signatures” of autism to help identify the underlying differences that could lead to a diagnosis

Alysson, you work with things called “brain organoids” explain what those are and could they help us in uncovering clues to the cause of autism and even possible therapies?

We blogged about this work when it was first published and you can read about it on our blog here.