The bootcamp helping in the fight against rare diseases

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Dr. Emil Kakkis at the Rare Entrepreneur Bootcamp

Imagine you or someone you love is diagnosed with a rare disease and then told, “There is no cure, there are no treatments and because it’s so rare no one is even doing any research into developing a treatment.” Sadly for millions of people that’s an all-too-common occurrence.

There are around 7,000 rare diseases affecting some 25-30 million Americans. Some of these are ultra-rare conditions where worldwide there may be only a few hundred people, or even a few dozen, diagnosed with it. And of all these rare diseases, only 5% have an approved therapy.

For the people struggling with a rare disease, finding a sense of hope in the face of all this can be challenging. Some say it feels as if they have been abandoned by the health care system. Others fight back, working to raise both awareness about the disease and funds to help support research to develop a treatment. But doing that without experience in the world of fund raising and drug development can pose a whole new series of challenges.

That’s where Ultragenyx comes into the picture. The company has a simple commitment to patients. “We aim to develop safe and effective treatments for many serious rare diseases as fast as we can, and we are committed to helping the whole rare disease community move forward by sharing our science and expertise to advance future development, whether by us or others.”

They live up to that commitment by hosting a Rare Entrepreneur Bootcamp. Every year they bring together a dozen or so patient or family organizations that are actively raising funds for a potential treatment approach and give them a 3-day crash course in what they’ll need to know to have a chance to succeed in rare disease drug development.

A panel discussion at the Rare Entrepreneur Bootcamp

Dr. Emil Kakkis, the founder of Ultragenyx, calls these advocates “warriors” because of all the battles they are going to face. He told them, “Get used to hearing no, because you are going to hear that a lot. But keep fighting because that’s the only way you get to ‘yes’.”

The bootcamp brings in experts to coach and advise the advocates on everything from presentation skills when pitching a potential investor, to how to collaborate with academic researchers, how to design a clinical trial, what they need to understand about manufacturing or intellectual property rights.

In a blog about the event, Arjun Natesan, vice president of Translational Research at Ultragenyx, wrote, “We are in a position to share what we’ve learned from bringing multiple drugs to market – and making the process easier for these organizations aligns with our goal of treating as many rare disease patients as possible. Our aim is to empower these organizations with guidance and tools and help facilitate their development of life-changing rare disease treatments.”

For the advocates it’s not just a chance to gain an understanding of the obstacles ahead and how to overcome them, it’s also a chance to create a sense of community. Meeting others who are fighting the same fight helps them realize they are not alone, that they are part of a bigger, albeit often invisible, community, working tirelessly to save the lives of their children or loved ones.  

CIRM also has a commitment to supporting the search for treatments for rare diseases. We are funding more than two dozen clinical trials, in addition to many earlier stage research projects, targeting rare conditions.

Turning back the clock to make old skin cells young again

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Dr. Diljeet Gill, photo courtesy Babraham Institute, Cambridge UK

Sometimes when I am giving public presentations people ask if stem cells are good for the face. I always say that if stem cells could help improve people’s faces would I look like this. It’s a line that gets a laugh but it’s also true. The ads you see touting stem cells as being beneficial for skin are all using plant stem cells. But now some new research has managed to turn back the clock for skin cells, and it might do a lot more than just help skin look younger.

Back in 2007 Japanese scientist Shinya Yamanaka discovered a way to turn ordinary skin cells back into an embryonic-like state, meaning those cells could then be turned into any other cell in the body. He called these cells induced pluripotent stem cells or iPSCs. Dr. Yamanaka was later awarded the Nobel Prize for Medicine for this work.

Using this work as their starting point, a team at Cambridge University in the UK, have developed a technique that can rewind the clock on skin cells but stop it less than a third of the way through, so they have made the cells younger but didn’t erase their identity as skin cells.

The study, published in the journal ELifeSciences, showed the researchers were able to make older skin cells 30 years younger. This wasn’t about restoring a sense of youthful beauty to the skin, instead it was about something far more important, restoring youthful function to the skin.

In a news release, Dr Diljeet Gill, a lead author on the study, said: “Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”

The team proved the potential for their work using fibroblasts, the most common kind of cell found in connective tissues such as skin. Fibroblasts are important because they produce collagen which helps provide support and structure to tissues and also helps in healing wounds. When the researchers examined the rejuvenated skin cells they found they were producing more collagen than cells that had not been rejuvenated. They also saw signs that these rejuvenated cells could help heal wounds better than the old cells.

The researchers also noted that this approach had an effect on other genes linked to age-related conditions, such Alzheimer’s disease and the development of cataracts.

The researchers acknowledge that this is all very early on, but the fact that they were able to make the cells behave and act like younger cells, without losing their identity as skin cells, holds tremendous promise not just for conditions affecting the skin, but for regenerative medicine as a whole.

Dr. Diljeet concluded: “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work.”

Promoting stem cell therapies, racial justice and fish breeding

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Jan Nolta, PhD, in her lab at UC Davis; Photo courtesy UC Davis

Working at CIRM you get to meet many remarkable people and Dr. Jan Nolta certainly falls into that category. Jan is the Director of the Stem Cell Program at UC Davis School of Medicine. She also directs the Institute for Regenerative Cures and is scientific director of both the Good Manufacturing Practice clean room facility at UC Davis and the California Umbilical Cord Blood Collection Program.

As if that wasn’t enough Jan is part of the team helping guide UC Davis’ efforts to expand its commitment to diversity, equity and inclusion using a variety of methods including telemedicine, to reach out into rural and remote communities.

She is on the Board of several enterprises, is the editor of the journal Stem Cells and, in her copious spare time, has dozens of aquariums and is helping save endangered species.

So, it’s no wonder we wanted to chat to her about her work and find out what makes her tick. Oh, and what rock bands she really likes. You might be surprised!

That’s why Jan is the guest on the latest edition of our podcast ‘Talking ‘Bout (re)Generation’.

I hope you enjoy it.

How a tiny patch is helping restore lasting vision

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Researchers are working on a stem cell-based retinal implant that could be used for people with with advanced dry age-related macular degeneration. (Photo/ Britney O. Pennington)

When Anna Kuehl began losing her vision, she feared losing the ability to read and go on long walks in nature—two of her favorite pastimes. Anna had been diagnosed with age-related macular degeneration, the leading cause of vision loss in the US. She lost the central vision in her left eye, which meant she could no longer make out people’s faces clearly, drive a car, or read the time on her watch.

Anna Kuehl

But a clinical trial funded by the California Institute for Regenerative Medicine  (CIRM) helped change that. And now, new data from that trial shows the treatment appears to be long lasting.

The treatment sprang out of research done by Dr. Mark Humayun and his team at USC. In collaboration with Regenerative Patch Technologies they developed a stem cell-derived implant using cells from a healthy donor. The implant was then placed under the retina in the back of the eye. The hope was those stem cells would then repair and replace damaged cells and restore some vision.

Dr. Mark Humayun, photo courtesy USC

In the past, using donor cells meant that patients often had to be given long-term immunosuppression to stop their body’s immune system attacking and destroying the patch. But in this trial, the patients were given just two months of immunosuppression, shortly before and after the implant procedure.

In a news story on the USC website, Dr. Humayun said this was an important advantage. “There’s been some debate on whether stem cells derived from a different, unrelated person would survive in the retina without long-term immunosuppression. For instance, if you were to receive a kidney transplant, long-term immunosuppression would be required to prevent organ rejection. This study indicates the cells on the retinal implant can survive for up to two years without long-term immunosuppression.”

Cells show staying power

When one of the patients in the clinical trial died from unrelated causes two years after getting the implant, the research team were able to show that even with only limited immunosuppression, there was no evidence that the patient’s body was rejecting the donor cells.

“These findings show the implant can improve visual function in some patients who were legally-blind before treatment and that the cells on the implant survive and remain functional for at least two years despite not being matched with those of the patient,” Humayun said.

For Anna Kuehl, the results have been remarkable. She was able to read an additional 17 letters on a standard eye chart. Even more importantly, she is able to read again, and able to walk and enjoy nature again.

Dr. Humayun says the study—published in the journal Stem Cell Reports—may have implications for treating other vision-destroying diseases. “This study addresses the debate over the viability of using mismatched stem cells — this shows that a mismatched stem cell derived implant can be safe and viable over multiple years.”

Meet the man who is unlocking the secrets of autism and sending mini-brains into space

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Dr. Alysson Muotri, UC San Diego

Normally if you meet someone who has a mini-fridge filled with brains, your first thought is to call the police. But when that someone is Dr. Alysson Muotri, a professor at U.C. San Diego, your second thought is “do tell me more.”

Alysson is a researcher who is fascinated by the human brain. He is working on many levels to try and unlock its secrets and give us a deeper understanding of how our brains evolved and how they work.

One of the main focuses of his work is autism (he has a son on the autism spectrum) and he has found a way to see what is happening inside the cells affected by autism—work that is already leading to the possibility of new treatments.

As for those mini-brains in his lab? Those are brain organoids, clumps of neurons and other cells that resemble—on a rudimentary level—our brains. They are ideal tools for seeing how our brains are organized, how the different cells signal and interact with each other. He’s already sent some of these brain organoids into space.

Brain in space

Alysson talks about all of this, plus how our brains compare to those of Neanderthals, on the latest episode of our podcast, Talking ‘Bout (re)Generation.

It’s a fascinating conversation. Enjoy.

Two Early-Stage Research Programs Targeting Cartilage Damage Get Funding from Stem Cell Agency

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Darryl D’Lima: Scripps Health

Every year millions of Americans suffer damage to their cartilage, either in their knee or other joints, that can eventually lead to osteoarthritis, pain and immobility. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two projects targeting repair of damaged cartilage.

The projects were among 17 approved by CIRM as part of the DISC2 Quest Discovery Program. The program promotes the discovery of promising new stem cell-based and gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.

Dr. Darryl D’Lima and his team at Scripps Health were awarded $1,620,645 to find a way to repair a torn meniscus. Every year around 750,000 Americans experience a tear in their meniscus, the cartilage cushion that prevents the bones in the knee grinding against each other. These injuries accelerate the early development of osteoarthritis, for which there is no effective treatment other than total joint replacement, which is a major operation. There are significant socioeconomic benefits to preventing disabling osteoarthritis. The reductions in healthcare costs are also likely to be significant.

The team will use stem cells to produce meniscal cells in the lab. Those are then seeded onto a scaffold made from collagen fibers to create tissue that resembles the knee meniscus. The goal is to show that, when placed in the knee joint, this can help regenerate and repair the damaged tissue.

This research is based on an earlier project that CIRM funded. It highlights our commitment to helping good science progress, hopefully from the bench to the bedside where it can help patients.

Dr. Kevin Stone: Photo courtesy Stone Research Foundation

Dr. Kevin Stone and his team at The Stone Research Foundation for Sports Medicine and Arthritis were awarded $1,316,215 to develop an approach to treat and repair damaged cartilage using a patient’s own stem cells.

They are using a paste combining the patient’s own articular tissue as well as Mesenchymal Stem Cells (MSC) from their bone marrow. This mixture is combined with an adhesive hydrogel to form a graft that is designed to support cartilage growth and can also stick to surfaces without the need for glue. This paste will be used to augment the use of a microfracture technique, where micro-drilling of the bone underneath the cartilage tear brings MSCs and other cells to the fracture site. The hope is this two-pronged approach will produce an effective and functional stem cell-based cartilage repair procedure.

If effective this could produce a minimally invasive, low cost, one-step solution to help people with cartilage injuries and arthritis.

The full list of DISC2 grantees is:

ApplicationTitlePrincipal Investigator and InstitutionAmount
DISC2-13212Preclinical development of an exhaustion-resistant CAR-T stem cell for cancer immunotherapy  Ansuman Satpathy – Stanford University    $ 1,420,200  
DISC2-13051Generating deeper and more durable BCMA CAR T cell responses in Multiple Myeloma through non-viral knockin/knockout multiplexed genome engineering  Julia Carnevale – UC San Francisco  $ 1,463,368  
DISC2-13020Injectable, autologous iPSC-based therapy for spinal cord injury  Sarah Heilshorn – Stanford University    $789,000
DISC2-13009New noncoding RNA chemical entity for heart failure with preserved ejection fraction.  Eduardo Marban – Cedars-Sinai Medical Center  $1,397,412  
DISC2-13232Modulation of oral epithelium stem cells by RSpo1 for the prevention and treatment of oral mucositis  Jeffrey Linhardt – Intact Therapeutics Inc.  $942,050  
DISC2-13077Transplantation of genetically corrected iPSC-microglia for the treatment of Sanfilippo Syndrome (MPSIIIA)  Mathew Blurton-Jones – UC Irvine    $1,199,922  
DISC2-13201Matrix Assisted Cell Transplantation of Promyogenic Fibroadipogenic Progenitor (FAP) Stem Cells  Brian Feeley – UC San Francisco  $1,179,478  
DISC2-13063Improving the efficacy and tolerability of clinically validated remyelination-inducing molecules using developable combinations of approved drugs  Luke Lairson – Scripps Research Inst.  $1,554,126  
DISC2-13213Extending Immune-Evasive Human Islet-Like Organoids (HILOs) Survival and Function as a Cure for T1D  Ronald Evans – The Salk Institute for Biological Studies    $1,523,285  
DISC2-13136Meniscal Repair and Regeneration  Darryl D’Lima – Scripps Health      $1,620,645  
DISC2-13072Providing a cure for sphingosine phosphate lyase insufficiency syndrome (SPLIS) through adeno-associated viral mediated SGPL1 gene therapy  Julie Saba – UC San Francisco  $1,463,400  
DISC2-13205iPSC-derived smooth muscle cell progenitor conditioned medium for treatment of pelvic organ prolapse  Bertha Chen – Stanford University  $1,420,200  
DISC2-13102RNA-directed therapy for Huntington’s disease  Gene Wei-Ming Yeo  – UC San Diego  $1,408,923  
DISC2-13131A Novel Therapy for Articular Cartilage Autologous Cellular Repair by Paste Grafting  Kevin Stone – The Stone Research Foundation for Sports Medicine and Arthritis    $1,316,215  
DISC2-13013Optimization of a gene therapy for inherited erythromelalgia in iPSC-derived neurons  Ana Moreno – Navega Therapeutics    $1,157,313  
DISC2-13221Development of a novel stem-cell based carrier for intravenous delivery of oncolytic viruses  Edward Filardo – Cytonus Therapeutics, Inc.    $899,342  
DISC2-13163iPSC Extracellular Vesicles for Diabetes Therapy  Song Li – UC Los Angeles  $1,354,928  

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.

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.

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

Getting under the skin of people with type 1 diabetes – but in a good way

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As someone with a family history of type 1 diabetes (T1D) I know how devastating the condition can be. I also know how challenging it can be to keep it under control and the consequences of failing to do that. Not maintaining healthy blood sugar levels can have a serious impact on the heart, kidney, eyes, nerves, and blood vessels. It can even be fatal.

Right now, controlling T1D means being careful about what you eat, when you eat and how much you eat. It also means regularly checking your blood throughout the day to see if the glucose level is too high or too low. If it’s too high you need to inject insulin; if it’s too low you need to take a fast-acting carbohydrate such as fruit juice or glucose to try and restore it to a healthy level.

That’s why two new approaches to T1D that CIRM has supported are so exciting. They both use small devices implanted under the skin that contain stem cells. The cells can both monitor blood sugar and, if it’s too high, secrete insulin to bring it down.

We sat down with two key members of the Encellin and ViaCyte teams, Dr. Crystal Nyitray and Dr. Manasi Jaiman, to talk about their research, how it works, and what it could mean for people with T1D. That’s in the latest episode of our podcast ‘Talking ‘Bout (re)Generation’.

I think you are going to enjoy it.

This is the size of the implant that ViaCyte is using.
This is the size of the implant Encellin is using

Dr. Crystal Nyitray, CEO & Co-founder Encellin

Dr. Manasi Jaiman, Vice President, Clinical Development ViaCyte