Overcoming obstacles and advancing treatments to patients

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UC Davis GMP Manufacturing facility: Photo courtesy UC Davis

When you are trying to do something that has never been done before, there are bound to be challenges to meet and obstacles to overcome. At the California Institute for Regenerative Medicine (CIRM) we are used to coming up with great ideas and hearing people ask “Well, how are you going to do that?”

Our new 5-year Strategic Plan is how. It’s the roadmap that will help guide us as we work to overcome critical bottlenecks in bringing regenerative medicine therapies to people in need.

Providing more than money

People often think of CIRM as a funding agency, providing the money needed to do research. That’s true, but it’s only part of the story. With every project we fund, we also offer a lot of support. That’s particularly true at the clinical stage, where therapies are being tested in people. Projects we fund in clinical trials don’t just get money, they also have access to:

  • Alpha Stem Cells Clinic Network – This is a group of specialized medical centers that have the experience and expertise to deliver new stem cell and gene therapies.
  • The CIRM Cell and Gene Therapy Center – This helps with developing projects, overcoming manufacturing problems, and offers guidance on working with the US Food and Drug Administration (FDA) to get permission to run clinical trials.
  • CIRM Clinical Advisory Panels (CAPs) – These are teams put together to help advise researchers on a clinical trial and to overcome problems. A crucial element of a CAP is a patient advocate who can help design a trial around the needs of the patients, to help with patient recruitment and retention.

Partnering with key stakeholders

Now, we want to build on this funding model to create new ways to support researchers in bringing their work to patients. This includes earlier engagement with regulators like the FDA to ensure that projects match their requirements. It includes meetings with insurers and other healthcare stakeholders, to make sure that if a treatment is approved, that people can get access to it and afford it.

In the past, some in the regenerative medicine field thought of the FDA as an obstacle to approval of their work. But as David Martin, a CIRM Board member and industry veteran says, the FDA is really a key ally.

“Turning a promising drug candidate into an approved therapy requires overcoming many bottlenecks… CIRM’s most effective and committed partner in accelerating this is the FDA.”

Removing barriers to manufacturing

Another key area highlighted in our Strategic Plan is overcoming manufacturing obstacles. Because these therapies are “living medicines” they are complex and costly to produce. There is often a shortage of skilled technicians to do the jobs that are needed, and the existing facilities may not be able to meet the demand for mass production once the FDA gives permission to start a clinical trial. 

To address all these issues CIRM wants to create a California Manufacturing Network that combines academic innovation and industry expertise to address critical manufacturing bottlenecks. It will also coordinate training programs to help build a diverse and expertly trained manufacturing workforce.

CIRM will work with academic institutions that already have their own manufacturing facilities (such as UC Davis) to help develop improved ways of producing therapies in sufficient quantities for research and clinical trials. The Manufacturing Network will also involve industry partners who can develop facilities capable of the large-scale production of therapies that will be needed when products are approved by the FDA for wider use.

CIRM, in collaboration with this network, will also help develop education and hands-on training programs for cell and gene therapy manufacturing at California community colleges and universities. By providing internships and certification programs we will help create a talented, diverse workforce that is equipped to meet the growing demands of the industry.

You can read more about these goals in our 2022-27 Strategic Plan.

Sharing ideas and data to advance regenerative medicine

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If Kindergarten kids can learn to share why can’t scientists?

When I was a kid, we were always told to share our toys. It was a good way of teaching children the importance of playing nice with the other kids and avoiding conflicts.

Those same virtues apply to science. Sharing data, knowledge and ideas doesn’t just create a sense of community. It also helps increase the odds that scientists can build on the knowledge gained by others to advance their own work, and the field as a whole.

That’s why advancing world class science through data sharing is one of the big goals in CIRM’s new Strategic Plan. There’s a very practical reason why this is needed. Although most scientists today fully appreciate and acknowledge the importance of data sharing, many still resist the idea. This is partly for competitive reasons: the researchers want to publish their findings first and take the credit.

But being first isn’t just about ego. It is also crucial in getting promotions, being invited to prestigious meetings, winning awards, and in some cases, getting the attention of biopharma. So, there are built-in incentives to avoiding data sharing.

That’s unfortunate because scientific progress is often dependent on collaboration and building upon the work of other researchers.

CIRM’s goal is to break down those barriers and make it easier to share data. We will do that by building what are called “knowledge networks.” These networks will streamline data sharing from CIRM-funded projects and combine that with research data from other organizations, publishers and California academic institutions. We want to create incentives for scientists to share their data, rather than keep it private.

We are going to start by creating a knowledge network for research targeting the brain and spinal cord. We hope this will have an impact on studying everything from stroke and Alzheimer’s to Parkinson’s and psychiatric disorders. The network will eventually cover all aspects of research—from the most basic science to clinical trials—because knowledge gained in one area can help influence research done in another.

To kick start this network, CIRM will partner with other funding agencies, disease foundations and research institutions to enable scientists to have access to this data such that data from one platform can be used to analyze data from another platform. This will amplify the power of data analysis and allow researchers to build upon the work of others rather than repeat already existing research.

As one of our Board members, Dr. Keith Yamamoto said in our Strategic Plan, “Making such data sharing and analysis across CIRM projects operational and widely accessible would leverage CIRM investments, serving the biomedical research enterprise broadly.”

It’s good for science, but ultimately and more importantly, it’s good for all of us because it will speed up the development of new approaches and new therapies for a wide range of diseases and disorders.

Visit this page to learn more about CIRM’s new 5-year Strategic Plan and stay tuned as we share updates on our 5-year goals here on The Stem Cellar.

How two California researchers are advancing world class science to develop real life solutions

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In our recently launched 5-year Strategic Plan, the California Institute for Regenerative Medicine (CIRM) profiled two researchers who have leveraged CIRM funding to translate basic biological discoveries into potential real-world solutions for devastating diseases.

Dr. Joseph Wu is director of the Stanford Cardiovascular Institute and the recipient of several CIRM awards. Eleven of them to be exact! Over the past 10 years, Dr. Wu’s lab has extensively studied the application of induced pluripotent stem cells (iPSCs) for cardiovascular disease modeling, drug discovery, and regenerative medicine. 

Dr. Wu’s extensive studies and findings have even led to a cancer vaccine technology that is now being developed by Khloris Biosciences, a biotechnology company spun out by his lab. 

Through CIRM funding, Dr. Wu has developed a process to produce cardiomyocytes (cardiac muscle cells) derived from human embryonic stem cells for clinical use and in partnership with the agency. Dr. Wu is also the principal investigator in the first-in-US clinical trial for treating ischemic heart disease. His other CIRM-funded work has also led to the development of cardiomyocytes derived from human induced pluripotent stem cells for potential use as a patch.

Over at UCLA, Dr. Lili Yang and her lab team have generated invariant Natural Killer T cells (iNKT), a special kind of immune system cell with unique features that can more effectively attack tumor cells. 

More recently, using stem cells from donor cord-blood and peripheral blood samples, Dr. Yang and her team of researchers were able to produce up to 300,000 doses of hematopoietic stem cell-engineered iNKT (HSC–iNKT) cells. The hope is that this new therapy could dramatically reduce the cost of producing immune cell products in the future. 

Additionally, Dr. Yang and her team have used iNKT cells to develop both autologous (using the patient’s own cells), and off-the-shelf anti-cancer therapeutics (using donor cells), designed to target blood cell cancers.

The success of her work has led to the creation of a start-up company called Appia Bio. In collaboration with Kite Pharma, Appia Bio is planning on developing and commercializing the promising technology. 

CIRM has been an avid supporter of Dr. Yang and Dr. Wu’s research because they pave the way for development of next-generation therapies. Through our new Strategic Plan, CIRM will continue to fund innovative research like theirs to accelerate world class science to deliver transformative regenerative medicine treatments in an equitable manner to a diverse California and the world.

Visit this page to learn more about CIRM’s new 5-year Strategic Plan and stay tuned as we share updates on our 5-year goals here on The Stem Cellar.

A CIRM-funded therapy for a deadly blood cancer gets approval for Phase 3 clinical trial

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Michael Wang, MD (right) of the Department of Lymphoma & Myeloma at MD Anderson Cancer Center will lead the Phase 3 clinical

Oncternal Therapeutics, Inc. is celebrating an encouraging milestone at the start of the new year following a successful End-of-Phase 2 meeting with the FDA. 

Specifically, the FDA agreed on key elements of the company’s potentially pivotal Phase 3 clinical trial of zilovertamab, which offers potential treatment advantages to patients suffering from relapsed or refractory mantle cell lymphoma (MCL). Zilovertamab (previously called cirmtuzumab because it was developed with CIRM fundingis the company’s investigational anti-ROR1 monoclonal antibody. 

Mantle cell lymphoma is an aggressive form of blood cancer that develops when white blood cells, which are a key component of our immune system and help fight infections, grow out of control. 

The California Institute for Regenerative Medicine (CIRM) funded an earlier-stage trial conducted by Oncternal Therapeutics in collaboration with UC San Diego. 

The Phase 3 clinical trial will be led by Dr. Michael Wang, of the Department of Lymphoma & Myeloma at MD Anderson Cancer Center. The trial will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo. All patients will continue receiving oral ibrutinib.  

The study (ZILO-301) will be conducted internationally in at least 50 centers experienced in treating MCL, and is expected to begin in the second quarter of 2022.  

The researchers hope the treatment will lead to progression-free survival for patients getting zilovertamab and that this will lead to FDA approval of the therapy. 

The company is also planning to conduct study ZILO-302, an open-label companion study of zilovertamab plus ibrutinib for patients who have progressive disease during the initial four months of ibrutinib monotherapy from Study ZILO-301. 

Read the full release of the study here and be sure to follow the Stem Cellar blog for more updates on the clinical trial.  

Teaching stem cells to play video games

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video games atari pong
Pong video game

Back when I was growing up, shortly after the extinction of the dinosaurs, there was a popular video game called Pong. It was, in fact, pretty much the only video game at the time. It was a pretty simple game. You moved a “paddle” to hit a ball and knock it back across the screen to your opponent. If your opponent missed it you won the point. It was a really simplified form of video ping pong (hence the name). 

So why am I telling you this? Well, researchers in the UK and Australia have devised a way of teaching blobs of brain cells how to play Pong. I kid you not. 

Playing Pong

What they did was turn stem cells into brain cells, as part of a system called Dishbrain. Using software, they helped these neurons or brain cells communicate with each other through electrical stimulation and recordings. 

In an article in Newsweek, (yup, Newsweek is still around) the researchers explained that using these electrical signals they could help the cells identify where the “ball” was. For example, if the signals came from the left that meant the “ball” was on the right. 

In the study they say: “Using this DishBrain system, we have demonstrated that a single layer of in vitro (in a dish) cortical neurons can self-organize and display intelligent and sentient behavior when embodied in a simulated game-world.” We have shown that even without a substantial filtering of cellular activity, statistically robust differences over time and against controls could be observed in the behavior of neuronal cultures in adapting to goal directed tasks.”

Now you might think this was just something the researchers dreamed up to pass time during COVID, but they say understanding how these brain cells can learn and respond could help them develop other methods of using neurons that might be even cooler than playing video games. 

The study is published in the journal BioRXiv

UCLA gene therapy offers children with LAD-1 a new chance at living a normal life

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Photo courtesy of Tamara Hogue/UCLA Broad Stem Cell Research Center

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare pediatric disorder that causes the immune system to malfunction, resulting in recurrent, often severe, bacterial and fungal infections as well as delayed wound healing. This is because of a missing protein that would normally enable white blood cells to stick to blood vessel walls- a crucial step that is needed before moving outside the vessel walls and into tissues to fight infections. If left undiagnosed and untreated, LAD-1 is fatal and most children with the disorder will die before the age of 2.

When Marley Gaskins was finally diagnosed with LAD-1 at age 8 (an extraordinary feat on its own) she had already spent countless hours hospitalized and required round the clock attention and care. The only possible cure was a risky bone marrow transplant from a matched donor, a procedure so rarely performed that there is no data to determine the survival rate.

In search of a better treatment option, Marley’s family came across a clinical trial for children with LAD-1 led by Dr. Donald Kohn, MD, a researcher in the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. 

The novel clinical trial, sponsored by Rocket Pharmaceuticals and CIRM, uses gene therapy in a treatment that works by harvesting the defective blood-making stem cells, correcting the mutation in a lab, and then transplanting the properly functioning cells back into the child’s body. The process eliminates the potential rejection risks of a bone marrow transplant because the corrected cells are the patient’s own.

For Marley’s family, the decision was a no-brainer. “I didn’t hesitate in letting her be a participant in the trial,” Marley’s mother, Tamara Hogue explains, “because I knew in my heart that this would give her a chance at having a normal life.”

In 2019, 9-year-old Marley became the first LAD-1 patient ever to receive the stem cell gene therapy. In the following year, five more children received the gene therapy at UCLA, including three siblings. And Last week, Dr. Kohn reported at the American Society of Hematology Annual Meeting and Exposition that all the children “remain healthy and disease-free”. 

More than two years out of treatment, Marley’s life and daily activities are no longer constricted by the frequent and severe infections that kept her returning to the hospital for months at a time. Instead, she enjoys being an average 12-year-old: going camping, getting her ears pierced, and most importantly, attending what she calls “big school” in the coming year. For patients and families alike, the gene therapy’s success has been like a rebirth. Doctors expect that the one-time therapy will keep LAD-1 patients healthy for life.

Researchers develop a stem cell-based implant for cartilage restoration and treating osteoarthritis

The Plurocart’s scaffold membrane seeded with stem cell-derived chondrocytes. Image courtesy of USC Photo/Denis Evseenko.

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Researchers at the Keck School of Medicine of USC have used a stem cell-based bio-implant to repair cartilage and delay joint degeneration in a large animal model. This paves the way to potentially treat humans with cartilage injuries and osteoarthritis, which occurs when the protective cartilage at the ends of the bones wears down over time. The disorder affects millions worldwide.

 The researchers are using this technology to manufacture the first 64 implants to be tested on humans with support from a $6 million grant from the California Institute for Regenerative Medicine (CIRM).

Researchers Dr. Denis Evseenko, and Dr. Frank Petrigliano led the development of the therapeutic bio-implant, called Plurocart. It’s composed of a scaffold membrane seeded with stem cell-derived chondrocytes, the cells responsible for producing and maintaining healthy articular cartilage tissue. 

In the study, the researchers implanted the Plurocart membrane into a pig model of osteoarthritis, resulting in the long-term repair of articular cartilage defects. Evseenko said the findings are significant because the implant fully integrated in the damaged articular cartilage tissue and survived for up to six months. “Previous studies have not been able to show survival of an implant for such a long time,” Evseenko added.

The researchers also found that the cartilage tissue generated was strong enough to withstand compression and elastic enough to accommodate movement without breaking.

Osteoarthritis, an often-painful disorder, can affect any joint, but most commonly affects those in our knees, hips, hands and spine. The USC researchers hope their implant will help prevent the development of arthritis and alleviate the need for invasive joint replacement surgeries.

“Many of the current options for cartilage injury are expensive, involve complex logistical planning, and often result in incomplete regeneration,” said Petrigliano. “Plurocart represents a practical, inexpensive, one-stage therapy that may be more effective in restoring damaged cartilage and improve the outcome of such procedures.”

Read the full study here and learn more about the CIRM grant here.

Lack of diversity leaves cloud hanging over asthma drug study

Asthma spacer, photo courtesy Wiki Media Creative Commons

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If you want to know if a new drug or therapy is going to work in the people it affects the most you need to test the drug or therapy in the people most affected by the disease. That would seem blindingly obvious, wouldn’t it? Apparently not.

Case in point. A new asthma medication, one that seemingly shows real promise in reducing attacks in children, was tested on an almost entirely white patient population, even though Black and Puerto Rican children are far more likely to suffer from asthma.

The study enrolled more than 400 children, between the ages of 6 and 11, with moderate to serious uncontrolled asthma and treated them with a medication called Dupixent. The results, published in the New England Journal of Medicine, were impressive. Children given Dupixent had an average drop in severe asthma attacks of 65 percent compared to children given a placebo.

The only problem is 90 percent of the children in the study were white. Why is that a problem? Because, according to the Asthma and Allergy Foundation of America, only 9.5 percent of white children have asthma, compared to 24 percent of Puerto Rican children and 18 percent of Black children. So, the groups most likely to suffer from the disease were disproportionately excluded from a study about a treatment for the disease.

Some people might think, “So what! If the medication works for one kid it will work for another, what does race have to do with it?” Quite a lot actually.

A study in the Journal of Allergy and Clinical Immunology concluded that: “Race/ethnicity modified the association between total IgE (an antibody in the blood that is a marker for asthma) and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans… Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations.”

The article concluded by calling for “more studies in diverse populations for equitable treatment of minority patients with asthma.” Something that clearly didn’t happen in the Dupixent study.

While that’s more than disappointing, it’s not surprising. A recent study of vaccine clinical trials in JAMA Network Open found that:

  • Overall, white individuals made up almost 80 percent of people enrolled.
  • Black individuals were represented only 10.6 percent of the time.
  • Latino participants were represented just 11.6 percent of the time. 

Additionally, in pediatric trials, Black participants were represented just over 10 percent of the time and Latino participants were represented 22.5 percent of the time. The study concluded by saying that “diversity enrollment targets are needed for vaccine trials in the US.”

I would expand on that, saying they are needed for all clinical trials. That’s one of the many reasons why we at the California Institute for Regenerative Medicine (CIRM) are making Diversity, Equity and Inclusion an important part of everything we do, such as requiring all applicants to have a written DEI plan if they want funding from us. Dr. Maria Millan, our President and CEO, recently co-authored an article in Nature Cell Biology, driving home the need for greater diversity in basic science and research in general.

DEI has become an important part of the conversation this past year. But the Dupixent trial shows that if we are truly serious about making it part of what we do, we have to stop talking and start acting.

Stem Cell Agency Board Approves Roadmap for Next Five Years

Dr. Maria Millan, CIRM’s President & CEO

It’s hard to get somewhere if you don’t know where you are going. Without a map you can’t plan a route to your destination. That’s why the CIRM Board approved a new Strategic Plan laying out a roadmap for the Stem Cell Agency for the next five years.

The plan builds on the achievements of Proposition 71, the voter approved ballot initiative that created the Agency in 2004, including:

  • Supporting 76 clinical trials.
  • Helping cure more than 40 children born with a rare, fatal immune disorder.
  • Creating the Alpha Clinics Network that specializes in the delivery of stem cell therapies to patients.
  • Training over 3000 students and scholars to become the future workforce of regenerative medicine.
  • Stimulating California’s economy with $10.7 Billion in additional sales revenue and the creation of 56,000 new jobs (between 2004-2018)

The passage of Proposition 14 in 2020 has positioned CIRM to continue to accelerate research from discovery to clinical; to drive innovative, real-world solutions resulting in transformative treatments for patients; and to ensure the affordability and accessibility of those treatments to a diverse community of patients in an equitable manner, including those often overlooked or underrepresented in the past.

“We achieved a lot in the last 15 years and this provides a solid foundation for our strategy to bring us to the new era of CIRM and to deliver the full potential of regenerative medicine, says Dr. Maria T. Millan, the President and CEO of CIRM. “This plan lays out a roadmap for us to overcome the challenges in developing transformative therapies and making them accessible and affordable in an equitable fashion to a diverse California. The plan will guide us in that work through the development of novel scientific endeavors, effective healthcare delivery models, and expanded education and training programs.”

The Strategic Plan is organized into three main themes:

  • Advance World Class Science – Foster a culture of collaborative science by creating knowledge networks and shared research tools and technologies that encourage and facilitate data and resource sharing.
  • Deliver Real World Solutions – Accelerate approval of therapies by optimizing our support models for CIRM-funded clinical trials with attention to including underserved communities; build the California Manufacturing Network to overcome manufacturing hurdles; and expand the Alpha Clinics network and create the Community Care Centers of Excellence to deliver therapies to a diverse patient population often in underserved communities.
  • Provide Opportunity for All – Build a racially, ethnically and experientially diverse and highly skilled workforce to support the growing regenerative medicine economy in California; deliver a roadmap for access and affordability of regenerative medicine for all California patients.

Reflecting these goals, CIRM’s new mission statement is: Accelerating world class science to deliver transformative regenerative medicine treatments in an equitable manner to a diverse California and world.

“We realize that these are ambitious goals but they are achievable,” says Dr. Millan, “If CIRM is going to continue to be a global leader in the field of regenerative medicine, and to live up to the faith shown in us by the people of California, we believe we have to aim high. We have a terrific team, a clear vision and a determination to fulfill our mission. And that’s what we intend to do.”

How some brilliant research may have uncovered a potential therapy for Alzheimer’s 

Dr. Nicole Koutsodendris, photo courtesy Gladstone Institutes

In the world of scientific research, the people doing clinical trials tend to suck up all the oxygen in the room. They’re the stars, the ones who are bringing potential therapies to patients. However, there’s another group of researchers who toil away in the background, but who are equally deserving of praise and gratitude. 

Dr. Lana Zholudeva, photo courtesy Gladstone Institutes

These are the scientists who do basic or discovery-level research. This is where all great therapies start. This is where a researcher gets an idea and tests it to see if it holds promise. A good idea and a scientist who asks a simple question, “I wonder if…..”  

Dr. Yadong Huang, Photo courtesy Gladstone Institutes

In our latest “Talking ‘Bout (re)Generation” podcast we talk to three researchers who are asking those questions and getting some truly encouraging answers. They are scientists at the Gladstone Institutes in San Francisco: one seasoned scientist and two young post-docs trying to make a name for themselves. And they might just have discovered a therapy that could help people battling Alzheimer’s disease. 

Enjoy the podcast.