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?

‘Mini lung’ model shows scientists early stages of new coronavirus infection

Representative image of three-dimensional human lung alveolar organoid showing alveolar stem cell marker, HTII-280 (red) and SARS-CoV-2 entry protein, ACE2 (green)
Image Credit: Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong

The development of organoid modeling has significantly expanded our understanding of human organs and the diseases that can affect them. For those unfamiliar with the term, an organoid is a miniaturized, simplified version of an organ produced that is also three dimensional.

Recently, scientists from the University of Cambridge and the Korea Advanced Institute Science and Technology (KAIST) were able to develop ‘mini lungs’ from donated tissue and use them to uncover the mechanisms behind the new coronavirus infection and the early immune response in the lungs.

SARS-CoV-2, the name of the coronavirus that causes COVID-19, first appears in the alveoli, which are tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide.

To better understand how SARS-CoV-2 infects the lungs and causes COVID-19, the team used donated tissue to extract a specific type of lung cell. They then reprogrammed these cells to an earlier stem cell-like state and used them to grow the lung organoids.

The team then infected the ‘mini lungs’ with a strain of SARS-CoV-2 taken from a patient in South Korea who was diagnosed with COVID-19 after traveling to Wuhan, China.

Within the newly infected lung organoids, the team observed that the virus began to replicate rapidly, reaching full cellular infection in just six hours. Replication allows the virus to spread the infection throughout the body to other cells and tissue. The infected cells also began to produce interferons, which are proteins that act as warning signals to healthy cells, telling them to activate their antiviral defenses. After two days, the interferons triggered an immune response and the cells started fighting back against infection. Two and a half days after infection, some of the alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.

In a news release, Dr. Joo-Hyeon Lee, co-senior author of this study, elaborates on how he hopes this study can help more vulnerable sections of the population.

“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue.”

The complete study was published in Cell Stem Cell.

CIRM has funded two discovery stage research projects that use lung organoids to look at potential treatments for COVID-19. One is being conducted by Dr. Brigitte Gomperts at UCLA and the other by Dr. Evan Snyder at the Sanford Burnham Prebys Medical Discovery Institute.

How stem cells are helping her win the fight of her life

We have all read about people who smoke a pack of cigarettes and drink a bottle of whiskey a day and somehow manage to live a long, healthy life. Then there are people like Sandra Dillon. She lived as healthy a life as you can imagine; she exercised a lot, ate a healthy diet and didn’t smoke. Yet at the age of 28 she was diagnosed with a rare and deadly form of blood cancer called myelofibrosis.

Sandra underwent the traditional forms of treatment but those proved ineffective and time seemed to be running out. Then she heard about a clinical trial for a new, experimental stem cell therapy, with Dr. Catriona Jamieson at the University of California San Diego.

Sandra says she wasn’t looking forward to it, but she was in a lot of pain, was getting much sicker and none of the treatments she tried was working.

“At the time I was actually quite afraid of seeing doctors or going to medical institutions. My experience had been rough, and I knew that I had to overcome my fear of going to hospitals and being treated. But it was a chance to have hope and to be on something that might work when there was nothing else available.”

Dr. Jamieson’s approach (CIRM helped support her early work in this area) had led to her identifying how abnormal gene activity was responsible for the progression of this form of blood cancer. With that knowledge she then identified a specific small molecule known to inhibit this mutant gene activity, and how it could halt the disease.

That’s what happened with Sandra. She says after years of pain and exhaustion, of fearing that she was running out of time, the treatment produced impressive results.

“It was pretty amazing. I had really low expectations from how sick I was and that this was experimental, and it was cancer and you expect it to be awful. And my experience was the opposite of what I’d expected. I started to feel incredible. The pain, after a few months, the side effects from my cancer started to come down.”

Today Sandra’s cancer is still in remission. She is back to her old, healthy, energetic self. She says she doesn’t consider herself a stem cell pioneer but is glad her participation in the trial might also benefit others.

“It’s helped me but the opportunity that it could also help other people is truly meaningful.”

The treatment she received was approved by the US Food and Drug Administration in 2019, the first approval for a therapy that had CIRM support.

I recently had the great pleasure of interviewing Sandra as part of our CIRM 2020 Grantee Meeting.

Delivering a protein to testes could help treat male infertility

Delivering a protein (red fluorescence) to mice testes with a fibroin nanoparticle-encapsulated cationic lipid complex (green) restored male fertility.
Credit: Adapted from ACS Nano 2020, DOI: 10.1021/acsnano.0c04936

For many couples that are ready to start a family, infertility, which is the inability to conceive children, can be a devastating setback. In fact, according to the Mayo Clinic, about 15% of couples are infertile. Of those couples experiencing infertility, one in three are issues related to male infertility, which often involves problems with sperm development.

However, researchers at Seoul National University in South Korea have found a way to deliver an important protein to mouse testes to improve sperm development. This is the first demonstration of direct delivery of proteins into the testes to treat male infertility, which could one day help people.

Male infertility is often associated with a lack of sperm in the semen. This can occur because of damage to the blood-testis barrier (BTB), which protects reproductive cells from harm. A protein named PIN1 is important for proper BTB function.

For this study, male mice were genetically engineered to lack PIN1, making them infertile. The researchers then developed a delivery system called Fibroplex, which consists of sphere-shaped nanoparticles. The team then inserted PIN1 into the Fibroplex, which was subsequently injected into the testes of the infertile mice.

The results were remarkable. The scientists found that the treatment had restored nearly normal PIN1 levels and sperm stem cell numbers in addition to repairing the BTB. The treated mice were also able to father a similar number of pups in comparison to normal mice while untreated, infertile mice weren’t able to reproduce at all. However, the treated mice were only able to successfully reproduce until about 5 months after treatment, at which point the PIN1 was no longer present.

The full results of this study were published in ACS Nano 2020.

Repairing damaged muscles

Close-up of the arm of a 70-year-old male patient with a torn biceps muscle as a result of a bowling injury; Photo courtesy Science Photo Library

In the time of coronavirus an awful lot of people are not just working from home they’re also working out at home. That’s a good thing; exercise is a great way to boost the immune system, stay healthy and deal with stress. But for people used to more structured workouts at the gym it can come with a downside. Trying new routines at home that look easy on YouTube, but are harder in practice could potentially increase the risk of injury.

A new study from Japan looks at what happens when you damage a muscle. It won’t help it heal faster, but it will at least let you understand what is happening inside your body as you sit there with ice on your arm and ibuprofen in your hand.

The researchers found that when you damage a muscle, for example by trying to lift too much weight or doing too many repetitions of one exercise, the damaged muscle fibers leak substances that activate nearby “satellite” stem cells. These satellite cells then flock to the site of the injury and help repair the muscle.

The team, from Kumamoto University and Nagasaki University in Japan, named the leaking substances “Damaged myofiber-derived factors” (DMDFs) – personally I think “Substances Leaked by Injured Muscles (SLIM) would be a much cooler acronym, but that’s just me. Gaining a deeper understanding of how DMDFs work might help lead to therapies for older people who have fewer satellite muscle cells, and also for conditions like muscular dystrophy and age-related muscular fragility (sarcopenia), where the number and function of satellite cells decreases.

In an article in Science Daily, Professor Yusuke Ono, the leader of the study, says it’s possible that DMDFs play an even greater role in the body:

“In this study, we proposed a new muscle injury-regeneration model. However, the detailed molecular mechanism of how DMDFs activate satellite cells remains an unclear issue for future research. In addition to satellite cell activation, DMDF moonlighting functions are expected to be diverse. Recent studies have shown that skeletal muscle secretes various factors that affect other organs and tissues, such as the brain and fat, into the bloodstream, so it may be possible that DMDFs are involved in the linkage between injured muscle and other organs via blood circulation. We believe that further elucidation of the functions of DMDFs could clarify the pathologies of some muscle diseases and help in the development of new drugs.”

The study appears in the journal Stem Cell Reports.

CIRM funded trial for LAD-I announces positive results

Leukocyte Adhesion Deficiency-I (LAD-I) is a rare pediatric disease caused by a mutation in a specific gene that causes low levels of a protein called CD18. Due to low levels of CD18, the adhesion of immune cells is affected, which negatively impacts the body’s ability to combat infections.

Rocket Pharmaceuticals has announced positive results from a CIRM-funded clinical trial that is testing a treatment that uses a gene therapy called RP-L201. The therapy uses a patient’s own blood stem cells and inserts a functional version of the gene.  These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.  

The two patients enrolled in the CIRM funded trial have shown restored levels of CD18. Previous studies have indicated that an increase in CD18 to 4-10% is associated with survival into adulthood. The two patients demonstrated CD18 levels that exceeded this threshold.

In a news release, Jonathan Schwartz, M.D. Chief Medical Officer and Senior Vice President of Rocket, elaborated on these positive results.

“Patients with LAD-I have markedly diminished expression of the integrin CD18 and suffer from life-threatening bacterial and fungal infections. Natural history studies indicate that an increase in CD18 expression to 4-10% is associated with survival into adulthood. The two patients enrolled in our Phase 1 trial demonstrated restored CD18 expression substantially exceeding this threshold. In addition, we continue to observe a durable treatment effect in the patient followed through one year, with improvement of multiple disease-related skin lesions after therapy and no further requirements for prophylactic anti-infectives.”

A model for success

Dr. Maria Millan, CIRM’s President & CEO

Funding models are rarely talked about in excited tones.  It’s normally relegated to the dry tomes of academia. But in CIRM’s case, the funding model we have created is not just fundamental to our success in advancing regenerative medicine in California, it’s also proving to be a model that many other agencies are looking at to see if they can replicate it.

A recent article in the journal Cell & Gene Therapy Insights looks at what the CIRM model does and how it has achieved something rather extraordinary.

Full disclosure. I might be a tad biased here as the article was written by my boss, Dr. Maria Millan, and two of my colleagues, Dr. Sohel Talib and Dr. Shyam Patel.

I won’t go into huge detail here (you can get that by reading the article itself) But the article “highlights 3 elements of CIRM’s funding model that have enabled California academic researchers and companies to de-risk development of novel regenerative medicine therapies and attract biopharma industry support.”

Those three elements are:

1. Ensuring that funding mechanisms bridge the entire translational “Valley of Death”

2. Constantly optimizing funding models to meet the needs of a rapidly evolving industry

3. Championing the portfolio and proactively engaging potential industry partners

As an example of the first, they point to our Disease Team awards. These were four-year investments that gave researchers with promising projects the time, support and funds they needed to not only develop a therapy, but also move it out of academia into a company and into patients.  Many of these projects had struggled to get outside investment until CIRM stepped forward. One example they offer is this one.

“CIRM Disease Team award funding also enabled Dr. Irving Weissman and the Stanford University team to discover, develop and obtain first-in-human clinical data for the innovative anti-CD47 antibody immunotherapy approach to cancer. The spin-out, Forty Seven, Inc., then leveraged CIRM funding as well as venture and public market financing to progress clinical development of the lead candidate until its acquisition by Gilead Sciences in April 2020 for $4.9B.”

But as the field evolved it became clear CIRM’s funding model had to evolve too, to better meet the needs of a rapidly advancing industry. So, in 2015 we changed the way we worked. For example, with clinical trial stage projects we reduced the average time from application to funding from 22 months to 120 days. In addition to that applications for new clinical stage projects were able to be submitted year-round instead of only once or twice a year as in the past.

We also created hard and fast milestones for all programs to reach. If they met their milestone funding continued. If they didn’t, funding stopped. And we required clinical trial stage projects, and those for earlier stage for-profit companies, to put up money of their own. We wanted to ensure they had “skin in the game” and were as committed to the success of their project as we were.

Finally, to champion the portfolio we created our Industry Alliance Program. It’s a kind of dating program for the researchers CIRM funds and companies looking to invest in promising projects. Industry partners get a chance to look at our portfolio and pick out projects they think are interesting. We then make the introductions and see if we can make a match.

And we have.

“To date, the IAP has also formally enrolled 8 partners with demonstrated commitment to cell and gene therapy development. The enrolled IAP partners represent companies both small and large, multi-national venture firms and innovative accelerators.

Over the past 18 months, the IAP program has enabled over 50 one-on-one partnership interactions across CIRM’s portfolio from discovery stage pluripotent stem cell therapies to clinical stage engineered HSC therapies.”

As the field continues to mature there are new problems emerging, such as the need to create greater manufacturing capacity to meet the growth in demand for high quality stem cell products. CIRM, like all other agencies, will also have to evolve and adapt to these new demands. But we feel with the model we have created, and the flexibility we have to pivot when needed, we are perfectly situated to do just that.

Miss the CIRM Grantee Meeting? Watch it online now!

Due to the ongoing coronavirus pandemic, CIRM converted its 2020 Grantee Meeting with UC Irvine & UC San Diego to a completely virtual format this year. Held on September 14 & 15, we brought together stem cell scientists and trainees that have received CIRM funding.  In addition to the complex science, we also heard from patients and patient advocates.

If you missed it, we have uploaded all the talks and sessions to our Youtube Channel. To make it more convenient to navigate, you can find all the talks in one place by checking out our CIRM Grantee Meeting 2020 Playlist.

If you want a more extensive breakdown of the talks and sessions, we’ve got you covered there too! We have organized the videos by sessions and speakers on the CIRM website, which you can access by clicking here. The Grantee Meeting this year covered a wide variety of sessions including COVID-19 clinical trials, neurodegenerative diseases, eye diseases, immune disorders, cancer, and much more.

Below are a few highlights:

In 2010 Sandra was diagnosed with a rare bone marrow cancer myelofibrosis. A drug developed with CIRM funding that targets cancer stem cells has given her a second chance at life. The drug, fedratinib, has received FDA approval and is now marketed as INREBIC©.

When Evie was born in 2012, she was diagnosed with a fatal immune disorder called ADA-SCID. Her mother, Alysia Vaccaro, spoke about how a CIRM funded stem cell and gene therapy clinical trial cured Evie and gave her daughter a new chance at life.

Could stem cells help reverse hair loss?

I thought that headline would grab your attention. The idea behind it grabbed my attention when I read about a new study in the journal Cell Metabolism that explored that idea and came away with a rather encouraging verdict of “perhaps”.

The research team from the University of Helsinki say that on average people lose 1.5 grams of hair every day, which over the course of a year adds up to more than 12 pounds (I think, sadly, this is the one area where I’m above average.) Normally all that falling hair is replaced by stem cells, which generate new hair follicles. However, as we get older, those stem cells don’t work as efficiently which explains why so many men go bald.

In a news release, lead author Sara Wickstrom says this was the starting point for their study.

“Although the critical role of stem cells in ageing is established, little is known about the mechanisms that regulate the long-term maintenance of these important cells. The hair follicle with its well understood functions and clearly identifiable stem cells was a perfect model system to study this important question.”

Previous studies have shown that after stem cells create new hair follicles they essentially take a nap (resume a quiescent state in more scientific parlance) until they are needed again. This latest study found that in order to do that the stem cells have to change their metabolism, reducing their energy use in response to the lower oxygen tissue around them. The team identified a protein called Rictor that appears to be the key in this process. Cells with low levels of Rictor were less able to wake up when needed and generate more hair follicles. Fewer replacements, bigger gaps in the scalp.

The team then created a mouse model to test their theory. Sure enough, mice with low or no Rictor levels were less able to regenerate hair follicles. Not surprisingly this was most apparent in older mice, who showed lower Rictor levels, decreased stem cell activity and greater hair loss.

Sara Wickstrom says this could point to new approaches to reversing the process.

“We are particularly excited about the observation that the application of a glutaminase inhibitor was able to restore stem cell function in the Rictor-deficient mice, proving the principle that modifying metabolic pathways could be a powerful way to boost the regenerative capacity of our tissues,”

It’s early days in the research so don’t expect them to be able to put the Hair Club for Men out of business any time soon. But a follicle-challenged chap can dream can’t he.

An Atlas of the Human Heart that May Guide Development of New Therapies

By Lisa Kadyk, PhD. CIRM Senior Science Officer

Illustration of a man’s heart – Courtesy Science Photo

I love maps; I still have auto club maps of various parts of the country in my car.  But, to tell the truth, those maps just don’t have as much information as I can get by typing in an address on my cell phone.  Technological advances in global positioning systems, cellular service, data gathering and storage, etc. have made my beloved paper maps a bit of a relic.  

Similarly, technological advances have enabled scientists to begin making maps of human tissues and organs at a level of detail that was previously unimaginable.  Hundreds of thousands of single cells can be profiled in parallel, examining expression of RNA and proteins.  These data, in combination with new three-dimensional spatial analysis techniques and sophisticated computational algorithms, allow high resolution mapping of all the cells in a given tissue or organ.

Given these new capabilities, an international “Human Cell Atlas Consortium” published a white paper in 2017 outlining plans and strategies to build comprehensive reference maps of all human cells, organ by organ.  The intent of building such an atlas is to give a much better understanding of the biology and physiology of normal human tissues, as well as to give new insights into the nature of diseases affecting those tissues and to point the way to developing new therapies. 

One example of this new breed of cartography was published September 24 in the journal Nature, in a paper called simply “Cells of the Human Heart”.   This tour-de-force effort was led by scientists from Harvard Medical School, the Wellcome Sanger Institute, the Max Delbruck Center for Molecular Medicine in Berlin and Imperial College, London.  These teams and their collaborators analyzed about 500,000 cells from six different regions of the healthy adult human heart, using post-mortem organs from 14 donors.  They examined RNA and protein expression and mapped the distribution of different types of cells in each region of the heart.  In addition, they made comparisons of male and female hearts, and identified cells expressing genes known to be associated with different types of heart disease.  

One of the take-home messages from this study is that there is a lot of cellular complexity in the heart – with 11 major cell types (examples include atrial and ventricular cardiomyocytes, fibroblasts and smooth muscle cells), as well as multiple subpopulations within each of those types.  Also notable is the different distribution of cells between the atria (which are at the top of the heart and receive the blood) and ventricles (which are on the bottom of the heart and pump blood out): on average, close to half of the cells in the ventricles are cardiomyocytes, whereas only a third of the cells in the atria are cardiomyocytes.  Finally, there is a significantly higher percentage of cardiomyocytes in the ventricles of women (56%) than in the ventricles of men (47%).    The authors speculate that this latter difference might explain the higher volume of blood pumped per beat in women and lower rates of cardiovascular disease.  

The authors gave a few examples of how their data can be used for a better understanding of heart disease.  For example, they identified a specific subpopulation of cardiomyocytes that expresses genes associated with atrial fibrillation, suggesting that the defect may be associated with those cells.   Similarly, they found that a specific neuronal cell type expresses genes that are associated with a particular ventricular dysfunction associated with heart failure.    In addition, the authors identified which cells in the heart express the highest levels of the SARS-CoV-2 receptor, ACE2, including pericytes, fibroblasts and cardiomyocytes.  

Now that these data are accessible for exploration at www.heartcellatlas.org, I have no doubt that many scientific explorers will begin to navigate to a more complete understanding of both the healthy and diseased heart, and ultimately to new treatments for heart disease.