A little history in the making by helping the tiniest patients

Dr. Diana Farmer stands with Dr. Aijun Wang and their UC Davis research team.

It’s appropriate that at the start of Women’s History Month, UC Davis’ Dr. Diana Farmer is making a little history of her own. She launched the world’s first clinical trial using stem cells to treat spina bifida before the child is born.

Spina bifida is a birth defect caused when a baby’s spinal cord fails to develop properly in the womb. In myelomeningocele, the most severe form of spina bifida, a portion of the spinal cord or nerves is exposed in a sac through an opening in the spine. Most people with myelomeningocele have changes in their brain structure, leg weakness, and bladder and bowel dysfunction. 

Illustration of spina bifida

While surgery can help, Dr. Farmer says it is far from perfect: “Currently, the standard of care for our patients is fetal surgery, which, while promising, still leaves more than half of children with spina bifida unable to walk independently. There is an extraordinary need for a treatment that prevents or lessens the severity of this devastating condition. Our team has spent more than a decade working up to this point of being able to test such a promising therapy.” 

The team at UC Davis – in a CIRM-funded study – will use a stem cell “patch” that is placed over the exposed spinal cord, then surgically close the opening, hopefully allowing the stem cells to regenerate and protect the spinal cord.

In a news release Dr. Aijun Wang, a stem cell bioengineer, says the team has been preparing for this trial for years, helping show in animals that it is safe and effective. He is hopeful it will prove equally safe and effective in people: “Our cellular therapy approach, in combination with surgery, should encourage tissue regeneration and help patients avoid devastating impairments throughout their lives.” 

Dr. Farmer says the condition, while rare, disproportionately affects Latinx babies and if the procedure works could have an enormous impact on their lives and the lives of their families: “A successful treatment for MMC would relieve the tremendous emotional and economic cost burden on families. We know it initially costs approximately $532,000 per child with spina bifida. But the costs are likely several million dollars more due to ongoing treatments, not to mention all the pain and suffering, specialized childcare, and lost time for unpaid caregivers such as parents.”

Here is video of two English bulldogs who had their spinal injuries repaired at UC Davis using stem cells. This was part of the research that led to the clinical trial led by Dr. Farmer and Dr. Wang.

Stem cell gene therapy for Fabry disease shows positive results in patients

Darren Bidulka rests after his modified blood stem cells were transplanted into him at the Foothills Medical Centre in Calgary in 2017, allowing him to stop his enzyme therapy. (From left): Dr. Jeffrey Medin, Medical College of Wisconsin, Dr. Aneal Khan, the experimental trial lead in Calgary, and Darren Bidulka. Image Credit: Darren Bidulka

Fabry disease is an X-linked genetic disorder that can damage major organs and shorten lifespan. Without a functional version of a gene called GLA, our bodies are unable to make the correct version of an enzyme that breaks down a fat, and that in turn can lead to problems in the kidneys, heart and brain. It is estimated that one person in 40,000 to 60,000 has the disease and it affects men more severely than women since men only have one copy of the X chromosome. Current treatment consists of enzyme therapy infusions every two weeks but there is currently no cure for Fabry disease. 

However, a Canadian research team is conducting the world’s first pilot study to treat Fabry disease using a stem cell gene therapy approach. The researchers collected the patient’s own blood stem cells and used gene therapy to insert copies of the fully functional gene into the stem cells, allowing them to make the correct version of the enzyme. The newly modified stem cells were then transplanted back into each patient.

Five men participated in this trial and the results so far have been very encouraging. After treatment with the stem cell gene therapy, all patients began producing the corrected version of the enzyme to near normal levels within one week. With these initial results, all five patients were allowed to stop their biweekly enzyme therapy infusions. So far, only three patients decided to do so and are stable.

In a news release, Darren Bidulka, the first patient to be treated in the study, talked about how life changing this stem cell gene therapy has been for him.

“I’m really happy that this worked. What an amazing result in an utterly fascinating experience. I consider this a great success. I can lead a more normal life now without scheduling enzyme therapy every two weeks. This research is also incredibly important for many patients all over the world, who will benefit from these findings.”

CIRM is no stranger to stem cell gene therapy and its potential having funded clinical trials in various areas such as severe combined immunodeficiency (bubble baby disease), cystinosis, sickle cell disease, and various others. The broad range of genetic diseases it has been used in to treat patients further highlights its importance in scientific research.

The full results of this study were published in Nature Communications.

Tipping our hat to the good guys (& gals)

A search on Google using the term “stem cell blogs” quickly produces a host of sites offering treatments for everything from ankle, hip and knee problems, to Parkinson’s disease and asthma. Amazingly the therapies for those very different conditions all use the same kind of cells produced in the same way. It’s like magic. Sadly, it’s magic that is less hocus pocus and more bogus bogus.

The good news is there are blogs out there (besides us, of course) that do offer good, accurate, reliable information about stem cells. The people behind them are not in this to make a quick buck selling snake oil. They are in this to educate, inform, engage and enlighten people about what stem cells can, and cannot do.

So, here’s some of our favorites.

The Niche

This blog has just undergone a face lift and is now as colorful and easy to read as it is informative. It bills itself as the longest running stem cell blog around. It’s run by UC Davis stem cell biologist Dr. Paul Knoepfler – full disclosure, we have funded some of Paul’s work – and it’s a constant source of amazement to me how Paul manages to run a busy research lab and post regular updates on his blog.

The power of The Niche is that it’s easy for non-science folk – like me – to read and understand without having to do a deep dive into Google search or Wikipedia. It’s well written, informative and often very witty. If you are looking for a good website to check whether some news about stem cells is real or suspect, this is a great place to start.

Stem Cell Battles

This site is run by another old friend of CIRM’s, Don Reed. Don has written extensively about stem cell research in general, and CIRM in particular. His motivation to do this work is clear. Don says he’s not a doctor or scientist, he’s something much simpler:

“No. I am just a father fighting for his paralyzed son, and the only way to fix him is to advance cures for everyone. Also, my mother died of breast cancer, my sister from leukemia, and I myself am a prostate cancer survivor. So, I have some very personal reasons to support the California Institute for Regenerative Medicine and to want state funding for stem cell and other regenerative medicine research to continue in California!”

The power of Don’s writing is that he always tells human stories, real tales about real people. He makes everything he does accessible, memorable and often very funny. If I’m looking for ways to explain something complex and translate it into everyday English, I’ll often look at Don’s work, he knows how to talk to people about the science without having their eyes cloud over.

A Closer Look at Stem Cells

This is published by the International Society for Stem Cell Research (ISSCR), the leading professional organization for stem cell scientists. You might expect a blog from such a science-focused organization to be heavy going for the ordinary person, but you’d be wrong.

A Closer Look at Stem Cells is specifically designed for people who want to learn more about stem cells but don’t have the time to get a PhD. They have sections explaining what stem cells are, what they can and can’t do, even a glossary explaining different terms used in the field (I used to think the Islets of Langerhans were small islands off the coast of Germany till I went to this site).

One of the best, and most important, parts of the site is the section on clinical trials, helping people understand what’s involved in these trials and the kinds of things you need to consider before signing up for one.

Signals

Of course, the US doesn’t have a monopoly on stem cell research and that’s reflected in the next two choices. One is the Signals Blog from our friends to the north in Canada. This is an easy-to-read site that describes itself as the “Insiders perspective on the world of stem cells and regenerative medicine.” The ‘Categories ‘dropdown menu allows you to choose what you want to read, and it gives you lots of options from the latest news to a special section for patients, even a section on ethical and legal issues. 

EuroStemCell

As you may have guessed from the title this is by our chums across the pond in Europe. They lay out their mission on page one saying they want to help people make sense of stem cells:

“As a network of scientists and academics, we provide independent, expert-reviewed information and road-tested educational resources on stem cells and their impact on society. We also work with people affected by conditions, educators, regulators, media, healthcare professionals and policymakers to foster engagement and develop material that meets their needs.”

True to their word they have great information on the latest research, broken down by different types of disease, different types of stem cell etc. And like CIRM they also have some great educational resources for teachers to use in the classroom.

U.C. San Diego Scientist Larry Goldstein Joins Stem Cell Agency’s Board

Larry Goldstein, PhD.

Larry Goldstein PhD, has many titles, one of which sums up his career perfectly, “Distinguished Professor”. Dr. Goldstein has distinguished himself on many fronts, making him an ideal addition to the governing Board of the California Institute for Regenerative Medicine (CIRM).

Dr. Goldstein – everyone calls him Larry – is a Cell Biologist, Geneticist and Neuroscientist. He worked with many colleagues to launch the UC San Diego Stem Cell program, the Sanford Consortium for Regenerative Medicine and the Sanford Stem Cell Clinical Center. He has received the Public Service Award from the American Society for Cell Biology and has had a Public Policy Fellowship named for him by the International Society for Stem Cell Research. He is a member of the American Academy of Arts and Sciences and last year was named a member of the prestigious National Academy of Sciences.

“I look forward to working with the ICOC and CIRM staff to ensure that the best and most promising stem cell research and medicine is fostered and funded,” Larry said.

For more than 25 years Larry’s work has targeted the brain and, in particular, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) better known as Lou Gehrig’s disease.

In 2012 his team was the first to create stem cell models for two different forms of Alzheimer’s, the hereditary and the sporadic forms. This gave researchers a new way of studying the disease, helping them better understand what causes it and looking at new ways of treating it.

He was appointed to the CIRM Board by Pradeep Khosla, the Chancellor of U.C. San Diego saying he is “gratified you are assuming this important role.”

Jonathan Thomas, JD, PhD., Chair of the CIRM Board, welcome the appointment saying “I have known Larry for many years and have nothing but the highest regard for him as a scientist, a leader, and a great champion of stem cell research. He is also an innovative thinker and that will be invaluable to us as we move into a second chapter in the life of CIRM.”

Larry was born in Buffalo, New York and grew up in Thousand Oaks, California. He graduated from UC San Diego with a degree in Biology in 1976 and from the University of Washington with a Ph. D. in Genetics in 1980. He joined the faculty in Cell and Developmental Biology at Harvard University in 1984 where he was promoted to Full Professor with tenure in 1990. He returned to UC San Diego and the Howard Hughes Medical Institute in 1993. After 45 years pursuing cutting edge lab-based research Larry is now transitioning to an administrative and executive role at UC San Diego where he will serve as the Senior Advisor for Stem Cell Research and Policy to the Vice Chancellor of Health Sciences.

He replaces David Brenner who is standing down after completing two terms on the Board.

De-stressing stem cells and the Bonnie & Clyde of stem cells

Dr. John Cashman

The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.

Researchers at the Human BioMolecular Research Institute (HBRI) and Stanford University, have reported on a compound that can trigger a cascade of events that create stress and ultimately impact Wnt’s ability to control the ability of cells to repair themselves.

In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”

The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.

“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Speaking of cancer….

Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.

In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.

In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”

So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.

They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.

The study is published in the journal Cell Reports.

Surviving with Joy

Dr. Tippi MacKenzie (left) of UCSF Benioff Children’s Hospital San Francisco, visits with newborn Elianna and parents Nichelle Obar and Chris Constantino. Photo by Noah Berger

Alpha thalassemia major is, by any stretch of the imagination, a dreadful, heart breaker of a disease. It’s caused by four missing or mutated genes and it almost always leads to a fetus dying before delivery or shortly after birth. Treatments are limited and in the past many parents were told that all they can do is prepare for the worst.

Now, however, there is new hope with new approaches, including one supported by CIRM, helping keep these children alive and giving them a chance at a normal life.

Thalassemias are a group of blood disorders that affect the way the body makes hemoglobin, which helps in carrying oxygen throughout the body. In alpha thalassemia major it’s the lack of alpha globin, a key part of hemoglobin, that causes the problem. Current treatment requires in blood transfusions to the fetus while it is still in the womb, and monthly blood transfusions for life after delivery, or a bone marrow transplant if a suitable donor is identified.

A clinical trial run by University of California San Francisco’s Dr. Tippi MacKenzie – funded by CIRM – is using a slightly different approach. The team takes stem cells from the mother’s bone marrow and then infuses them into the fetus. If accepted by the baby’s bone marrow, these stem cells can then mature into healthy blood cells. The hope is that one day this method will enable children to be born with a healthy blood supply and not need regular transfusions.

Treating these babies, saving their lives, is the focus of a short film from UCSF called “Surviving with Joy”. It’s a testament to the power of medicine, and the courage and resilience of parents who never stopped looking for a way to help their child.

Tissues are optional but advised.

CIRM funded researchers discover link between Alzheimer’s gene and COVID-19

Dr. Yanhong Shi (left) and Dr. Vaithilingaraja Arumugaswami (right)

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.

It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19.  In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus.  One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.

It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grant and $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center.  The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.

At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain.  Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.  

The team first created neurons and astrocytes.  Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them.  The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients.  The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.

Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain.  They were able to create two different organoid models: one that contained astrocytes and one without them.  They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model. 

The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2.  They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient.  Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4.  Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral.  The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.

The results were astounding.  The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes.  Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes. 

“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”

In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes.  They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death.  For neurons, it was able to rescue them from steadily losing their function and even dying. 

The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19.  Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after. 

“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami.  “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”

The full results to this study were published in Cell Stem Cell.

Month of CIRM – Our Therapeutics Team Goes Hunting

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we have a guest blog by CIRM Senior Science Officer Lisa Kadyk, outlining how she and her colleagues actively search for the best science to fund.

Lisa Kadyk, Ph.D.

Hi everyone,

This is Lisa Kadyk, a Science Officer from the CIRM Therapeutics team, here to tell you about some of the work our team does to support the CIRM mission of accelerating stem cell treatments to patients with unmet medical needs.  Our job involves seeking out and recruiting great scientists to apply to CIRM and supporting those we fund.

Therapeutics team members manage both the awards that fund the final preclinical studies required before testing a therapeutic in a clinical trial (CLIN1), and the awards that fund the clinical trials themselves (CLIN2). 

I mentioned above that we actively recruit new applicants for our CLIN1 and CLIN2 awards – which is not an activity that is typical of most funding agencies – so why and how do we do this?  

It all comes down to our mission of accelerating the development of therapies to help patients with unmet medical needs.  It turns out that there are many potential applicants developing cutting edge therapies who don’t know much or anything about CIRM, and the ways we can help them with getting those therapies to the clinic and through clinical trials.    So, to bridge this gap, we Science Officers attend scientific conferences, read the scientific literature and meet regularly with each other to stay abreast of new therapeutic approaches being developed in both academia and industry, with the goal of identifying and reaching out to potential applicants about what CIRM has to offer. 

What are some of the things we tell potential applicants about how partnering with CIRM can help accelerate their programs?   First of all, due to the efforts of a very efficient Review team, CIRM is probably the fastest in the business for the time between application and potential funding.  It can be as short as three months for a CLIN1 or CLIN2 application to be reviewed by the external Grants Working Group and approved by the CIRM Board, whereas the NIH (for example) estimates it takes seven to ten months to fund an application.   Second, we have frequent application deadlines (monthly for CLIN1 and CLIN2), so we are always available when the applicant is ready to apply.  Third, we have other accelerating mechanisms in place to help grantees once they’ve received funding, such as the CIRM Alpha Stem Cell Clinics network of six clinical sites throughout California (more efficient clinical trial processes and patient recruitment) and Clinical Advisory Panels (CAPs) – that provide technical, clinical or regulatory expertise as well as patient advocate guidance to the grantee.  Finally, we Science Officers do our best to help every step of the way, from application through grant closeout.

We now feel confident that our recruitment efforts, combined with CIRM’s more efficient funding pipeline and review processes, are accelerating development of new therapies.  Back in 2016, a new CIRM Strategic Plan included the goal of recruiting 50 successful (i.e., funded) clinical trial applicants within five years.  This goal seemed like quite a stretch, since CIRM had funded fewer than 20 clinical trials in the previous ten years.  Fast-forward to the end of 2020, and CIRM had funded 51 new trials in those five years, for a grand total of 68 trials.    

Now, with the passage of Proposition 14 this past November, we are looking forward to bringing more cell and gene therapeutic candidates into clinical trials.   If you are developing one yourself, feel free to let us know… or don’t be surprised if you hear from us!  

CIRM-Funded Project Targeting Sickle Cell Disease Gets Green Light for Clinical Trial

Dr. Matthew Porteus

The US Food and Drug Administration (FDA) has granted Investigational New Drug (IND) permission enabling Graphite Bio to test the investigational, potentially revolutionary gene editing therapy GPH101 developed under the supervision of Matthew Porteus, MD, PhD, in a clinical trial for people with sickle cell disease (SCD).

The California Institute for Regenerative Medicine (CIRM) has been supporting this project with a $5.2 million grant, enabling Dr. Porteus and his team at the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University to conduct the preclinical manufacturing and safety studies required by the FDA.

“We congratulate the Graphite Bio team for obtaining the IND, a critical step in bringing the GPH101 gene therapy forward for Sickle Cell Disease,” says Dr. Maria T. Millan, CIRM’s President & CEO. “CIRM is committed to the national Cure Sickle Cell initiative and are delighted that this technology, the product of CIRM funded research conducted by Dr. Porteus at Stanford, is progressing to the next stage of development”

Sickle cell disease is caused by a genetic mutation that turns normally smooth, round red blood cells into rigid, sickle shaped cells. Those cells clump together, clogging up blood vessels, causing intense pain, damaging organs and increasing the risk of strokes and premature death. There are treatments that help control the damage, but the only cure is a bone marrow stem cell transplant, which can only happen if the patient has a stem cell donor (usually a close relative) who has matching bone marrow.  

The investigational therapy GPH101 harnesses the power of CRISPR and natural DNA repair mechanisms to cut out the single mutation in the sickle globin gene and paste in the correct “code.” Correction of this mutation would reverse the defect and result in healthy non-sickling red blood cells.  

CEDAR, a Phase 1/2, multi-center, open-label clinical study is designed to evaluate the safety, preliminary efficacy and pharmacodynamics of GPH101 in adult and adolescent patients with severe SCD.

For patient advocate Nancy Rene, the news is personal: “It’s always exciting to hear about the progress being made in sickle cell research.  If successful it will mean that my grandson, and especially other young adults, can look forward to a life free of pain and organ damage.  They can actually begin to plan their lives, thinking about careers and families. I want to thank Dr. Porteus and all of the scientists who are working so hard for people with sickle cell disease. This is wonderful news.”

CIRM has funded four clinical trials for Sickle Cell Disease using different approaches and has a unique partnership with the National Heart, Lung and Blood Institutes under the NIH “Cure Sickle Cell” initiative.