Overcoming obstacles and advancing treatments to patients

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

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.

CIRM-funded stem cell clinical trial patients: Where are they now?

Ronnie with his parents Pawash Priyank and Upasana Thakur.

Since its launch in 2004, the California Institute for Regenerative Medicine (CIRM) has been a leader in growing the stem cell and regenerative medicine field while keeping the needs of patients at the core of its mission. 

To date, CIRM has:  

  • Advanced stem cell research and therapy development for more than 75 diseases. 
  • Funded 76 clinical trials with 3,200+ patients enrolled. 
  • Helped cure over 40 children of fatal immunological disorders with gene-modified cell therapies. 

One of these patients is Ronnie, who just days after being born was diagnosed with severe combined immunodeficiency (SCID), a rare immune disorder that is often fatal within two years. 

A recent photo of Ronnie enjoying a day at the beach.

Fortunately, doctors told his parents about a CIRM-funded clinical trial conducted by UC San Francisco and St. Jude Children’s Hospital. Doctors took some of Ronnie’s own blood stem cells and, in the lab, corrected the genetic mutation that caused the condition. They then gave him a mild dose of chemotherapy to clear space in his bone marrow for the corrected cells to be placed and to grow. Over the next few months, the blood stem cells created a new blood supply and repaired Ronnie’s immune system. He is now a happy, healthy four-year-old boy who loves going to school with other children. 

Evie Junior participated in a CIRM-funded clinical trial in 2020. Photo: Jaquell Chandler

Another patient, Evie Junior, is pioneering the search for a cure for sickle cell disease: a painful, life-threatening condition.  

In July of 2020, Evie took part in a CIRM-funded clinical trial where his own blood stem cells were genetically modified to overcome the disease-causing mutation. Those cells were returned to him, and the hope is they’ll create a sickle cell-free blood supply. Evie hasn’t had any crippling bouts of pain or had to go to the hospital since his treatment.

To demonstrate treatment efficacy, study investigators will continue to monitor the recovery of Evie, Ronnie, and others who participate in clinical trials. 

CIRM’s new strategic plan seeks to help real life patients like Ronnie and Evie by optimizing its clinical trial funding partnership model to advance more therapies to FDA for approval.  

In addition, CIRM will develop ways to overcome manufacturing hurdles for the delivery of regenerative medicine therapies and create Community Care Centers of Excellence that support diverse patient participation in the rapidly maturing regenerative medicine landscape. Stay tuned as we cover these goals here on The Stem Cellar. 

To learn more about CIRM’s approach to deliver real world solutions for patients, check out our new 5-year strategic plan.  

Sharing ideas and data to advance regenerative medicine

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

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.

Empowering and connecting California’s research ecosystem through shared labs

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

A shared stem cell laboratory at UCLA

The California Institute for Regenerative Medicine (CIRM) has set ambitious goals in its new 5-year strategic plan. Made possible by renewed funding through Proposition 14, the plan lays out a roadmap for CIRM as the agency continues to advance world class science, deliver real world solutions, and provide opportunity for all.

In regenerative medicine (and many other fields), the lack of protocol standardization and lack of analytical toolkits make it difficult to access novel and reliable technology platforms.

CIRM recognizes these limitations, and as a response, the Agency has made it a goal in the “Prop 14 era” to develop next-generation competency hubs that empower and connect California’s research ecosystem.

One example of such competency hubs is the shared labs. The concept of shared labs isn’t new to CIRM. In fact, CIRM has awarded a total of 17 shared research laboratory grants to academic and nonprofit research institutions to provide lab space for innovative stem cell research and training.

CIRM will expand this shared lab model by creating networks of specialized competency hubs that offer knowledge and/or materials in cell and gene therapy development. These hubs will encourage collaborations and provide intra- and inter-institutional access to various competencies by sharing facilities, training, equipment, materials, protocols, and/or expertise.

As an example, a disease modeling competency hub would provide access to innovative models used to study diseases, collaborative researchers, shared facilities for conducting research, equipment and training programs for deriving or differentiating cell lines, etc. These collaborative environments would encourage researchers to work together with a team science approach, which would significantly accelerate discovery and therapy development.

Some of these hubs will also serve as a workforce training program for local and neighboring institutions. Most California state universities and community colleges have neither the financial nor experiential bandwidth for innovative research. They may, however, harbor a potentially diverse future workforce who could learn these techniques and use the technology platforms for small scale research. Training may also trigger the interest of the future workforce in pursuing the field of regenerative medicine.  

The competency hubs will also constitute part of the CIRM collaborative ecosystem making all their data available through the CIRM data infrastructure hub, also known as CIRM knowledge networks.

Finally, the network of competency hubs will greatly benefit the people of California by expanding geographic access to diverse communities and providing researchers with a unique opportunity of exposure to state-of-the-art platforms.

Visit this page to learn more about CIRM’s new 5-year Strategic Plan, and stay tuned as we share progress 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

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

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

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

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

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

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

One more good reason to exercise

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

As we start the New Year with a fervent hope that it’s better than the last two, many people are making a resolution to get more exercise. A new study suggests that might not just benefit the body, it could also help the brain. At least if you are a mouse.

Researchers at the University of Queensland Brain Institute found that 35 days of exercise could improve brain function and memory.

In an interview in Futurity, Dan Blackmore, one of the lead researchers on the study, says they not only showed the benefits of exercise, but also an explanation for why it helps.

“We tested the cognitive ability of elderly mice following defined periods of exercise and found an optimal period or ‘sweet spot’ that greatly improved their spatial learning. We found that growth hormone (GH) levels peaked during this time, and we’ve been able to demonstrate that artificially raising GH in sedentary mice also was also effective in improving their cognitive skills. We discovered GH stimulates the production of new neurons in the hippocampus—the region of the brain critically important to learning and memory.

The study was published in the journal iScience.

Obviously, this is great for mice, but they hope that future research could show similar benefits for people. But don’t wait for that study to come out, there’s already plenty of evidence that exercising has terrific benefits for the body. Here’s just seven ways it can give you a boost.

The Most Read Stem Cellar Blog Posts of 2021

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

This year was a momentous one for the California Institute for Regenerative Medicine (CIRM). We celebrated the passage of Proposition 14, and as a result, introduced our new strategic plan and added a group of talented individuals to our team.  

We shared our most exciting updates and newsworthy stories—topics ranging from stem cell research to diversity in science—right here on The Stem Cellar. Nearly 100,000 readers followed along throughout the year! 

In case you missed them, here’s a recap of our most popular blogs of 2021. We look forward to covering even more topics in 2022 and send a sincere thank you to our wonderful Stem Cellar readers for tuning in!  

Image courtesy of ViaCyte
  1. Type 1 Diabetes Therapy Gets Go-Ahead for Clinical Trial 
    This past year, ViaCyte and CRISPR Therapeutics put their heads together to develop a novel treatment for type 1 diabetes (T1D). The result was an implantable device containing embryonic stem cells that develop into pancreatic progenitor cells, which are precursors to the islet cells destroyed by T1D. The hope is that when this device is transplanted under a patient’s skin, the progenitor cells will develop into mature insulin-secreting cells that can properly regulate the glucose levels in a patient’s blood. 
CIRM’s new General Counsel Kevin Marks
  1. CIRM Builds Out World Class Team With 5 New hires 
    After the Passage of Proposition 14 in 2020, CIRM set ambitious goals as part of our new strategic plan. To help meet these goals and new responsibilities, we added a new group of talented individuals with backgrounds in legal, finance, human resources, project management, and more. The CIRM team will continue to grow in 2022, as we add more team members who will work to fulfil our mission of accelerating world class science to deliver transformative regenerative medicine treatments in an equitable manner to a diverse California and world. 
Image source: Doug Blackiston
  1. Meet Xenobots 2.0 – the Next Generation of Living Robots 
    In 2020, we wrote about how researchers at the University of Vermont and Tufts University were able to create what they call xenobots – the world’s first living, self-healing robots created from frog stem cells. Fast forward to 2021: the same team created an upgraded version of these robots that they have dubbed Xenobots 2.0. These upgraded robots can self-assemble a body from single cells, do not require muscle cells to move, and demonstrate the capability to record memory. Interesting stuff! 
Pictured: Clive Svendsen, Ph.D.
  1. CIRM Board Approves New Clinical Trial for ALS 
    In June, CIRM’s governing Board awarded $11.99 million to Cedars-Sinai to fund a clinical trial for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Clive Svendsen, Ph.D. and his team will be conducting a trial that uses a combined cell and gene therapy approach as a treatment for ALS. The trial builds upon CIRM’s first ALS trial, also conducted by Cedars-Sinai and Svendsen. 
Image courtesy of Karolina Grabowska
  1. COVID is a Real Pain in the Ear 
    Viral infections are a known cause of hearing loss and other kinds of infection. That’s why before the pandemic started, Dr. Konstantina Stantovic at Massachusetts Eye and Ear and Dr. Lee Gherke at MIT had been studying how and why things like measles, mumps and hepatitis affected people’s hearing. After COVID hit, they heard reports of patients experiencing sudden hearing loss and other problems, so they decided to take a closer look. 

And there you have it: The Stem Cellar’s top blog posts of 2021! If you’re looking for more ways to get the latest updates from The Stem Cellar and CIRM, follow us on social media on FacebookTwitterLinkedIn, and Instagram

How do Zebrafish grow ears? It’s quite transparent

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

Zebrafish

One of the hopes of regenerative medicine is that one day we will be able to use stem cells to regrow damaged organs, avoiding the need for a transplant. It’s a fascinating idea, supported in part by the ability of some creatures, such as Axolotls and salamanders, to regrow parts of their anatomy that they have lost.

But there’s quite a leap from a lizard to a human and bridging that gap is proving far from easy. One of the problems is simply understanding how cells know what to do to form the correct shape for the organ. Even something as relatively simple as an ear is incredibly complex.

However, researchers at Harvard Medical School have discovered a way to replicate how cells form into flexible sheets, so they can be folded into the delicate shape of tubes in the inner ear. They did this by studying Zebrafish. Why? In an article in Genetic Engineering and Biology News Dr. Akankshi Munjal, PhD, first author of the paper, said the reason was simple.

Akankshi Munjal, PhD, first author of the paper; Photo courtesy Harvard Medical School

“Zebrafish are transparent, so we just stick them under a microscope and look at this entire process from a single cell to a larva that can swim and has all its parts.”

Because they could watch the Zebrafish develop in real time, they were able to observe what the cells were doing at any point simply by looking at the fish under a microscope. Another advantage is that in Zebrafish the semicircular canals of the inner ear – tubes that help them maintain balance and orient themselves – form close to the surface, making it even easier to see what was going on.

In the study, published in the journal Cell, the researchers say it appears that a combination of pressure generated by hyaluronic acid, which acts as a cushion and lubricant between tissues, and molecular tethers between cells help direct flat sheets of cells into tubes and other shapes.

Dr. Sean Megason, one of the authors of the paper, said that knowing the mechanism at work is really important. “Right now tissue engineers are trying to build tissues without knowing how cells normally do this during embryonic development. We want to define these rules such that cells can be programmed to assemble into any desired pattern and shape. This work shows a new way in which cells can generate force to bend tissues into the right shape.”

The researchers say if they can understand how cells work together to create these complex shapes they may be better able to replicate that process in the lab, and grow ears, parts of ears or even other organs for people.