Stem cell research reveals path to schizophrenia

3d illustration of brain nerve cells – Photo courtesy Science Photo

If you don’t know what’s causing a problem it’s hard to come up with a good way to fix it. Mental health is the perfect example. With a physical illness you can see what the problem is, through blood tests or x-rays, and develop a plan to tackle it. But with the brain, that’s a lot harder. You can’t autopsy a brain while someone is alive, they tend to object, so you often only see the results of a neurological illness when they’re dead.

And, says Consuelo Walss-Bass, PhD, a researcher at the University of Texas Health Science Center at Houston (UTHealth), with mental illness it’s even more complicated.

“Mental health research has lagged behind because we don’t know what is happening biologically. We are diagnosing people based on what they are telling us. Even postmortem, the brain tissue in mental health disorders looks perfectly fine. In Alzheimer’s disease, you can see a difference compared to controls. But not in psychiatric disorders.”

So Wals-Bass and her team came up with a way to see what was going on inside the brain of someone with schizophrenia, in real time, to try and understand what puts someone at increased risk of the disorder.

In the study, published in the journal Neuropsychopharmacology, the researchers took blood samples from a family with a high incidence of schizophrenia. Then, using the iPSC method, they turned those cells into brain neurons and compared them to the neurons of individuals with no family history of schizophrenia. In effect, they did a virtual brain biopsy.

By doing this they were able to identify five genes that had previously been linked to a potential higher risk of schizophrenia and then narrow that down further, highlighting one gene called SGK1 which blocked an important signalling pathway in the brain.

In a news release, Walss-Bass says this findings could have important implications in treating patients.

“There is a new antipsychotic that just received approval from the Food and Drug Administration that directly targets the pathway we identified as dysregulated in neurons from the patients, and several other antipsychotics also target this pathway. This could help pinpoint who may respond better to treatments.”

Finding the right treatment for individual patients is essential in helping them keep their condition under control. A study in the medical journal Lancet estimated that six months after first being prescribed common antipsychotic medication, as many as 50% of patients are either taking the drugs haphazardly or not at all. That’s because they often come with unpleasant side effects such as weight gain, drowsiness and a kind of restless anxiety.

By identifying people who have specific gene pathways linked to schizophrenia could help us better tailor medications to those who will benefit most by them.

“Mini-brains” model an autism spectrum disorder and help test treatments

Alysson Muotri, PhD, professor and director of the Stem Cell Program at UC San Diego School of Medicine
and member of the Sanford Consortium for Regenerative Medicine.
Image credit: UC San Diego Health

Rett syndrome is a rare form of autism spectrum disorder that impairs brain development and causes problems with movement, speech, and even breathing. It is caused by mutations in a gene called MECP2 and primarily affects females. Although there are therapies to alleviate symptoms, there is currently no cure for this genetic disorder.

With CIRM funding ($1.37M and $1.65M awards), Alysson Muotri, PhD and a team of researchers at the University of California San Diego School of Medicine and Sanford Consortium for Regenerative Medicine have used brain organoids that mimic Rett syndrome to identify two drug candidates that returned the “mini-brains” to near-normal. The drugs restored calcium levels, neurotransmitter production, and electrical impulse activity.

Brain organoids, also referred to as “mini-brains”, are 3D models made of cells that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study changes in physical structure or gene expression over time.

Dr. Muotri and his team created induced pluripotent stem cells (iPSCs), a type of stem cell that can become virtually any type of cell. For the purposes of this study, they were created from the skin cells of Rett syndrome patients. The newly created iPSCs were then turned into brain cells and used to create “mini-brains”, thereby preserving each Rett syndrome patient’s genetic background. In addition to this, the team also created “mini-brains” that artificially lack the MECP2 gene, mimicking the issues with the same gene observed in Rett syndrome.

Lack of the MECP2 gene changed many things about the “mini-brains” such as shape, neuron subtypes present, gene expression patterns, neurotransmitter production, and decreases in calcium activity and electrical impulses. These changes led to major defects in the emergence of brainwaves.

To correct the changes caused by the lack of the MECP2 gene, the team treated the brain organoids with 14 different drug candidates known to affect various brain cell functions. Of all the drugs tested, two stood out: nefiracetam and PHA 543613. The two drugs resolved nearly all molecular and cellular symptoms observed in the Rett syndrome “mini-brains”, with the number active neurons doubling post treatment.

The two drugs were previously tested in clinical trials for the treatment of other conditions, meaning they have been shown to be safe for human consumption.

In a news release from UC San Diego Health, Dr. Muotri stresses that although the results for the two drugs are promising, the end treatment for Rett syndrome may require a multi-drug cocktail of sorts.

“There’s a tendency in the neuroscience field to look for highly specific drugs that hit exact targets, and to use a single drug for a complex disease. But we don’t do that for many other complex disorders, where multi-pronged treatments are used. Likewise, here no one target fixed all the problems. We need to start thinking in terms of drug cocktails, as have been successful in treating HIV and cancers.”

The full results of this study were published in EMBO Molecular Medicine.

Persistence pays off in search for clue to heart defects

A team of scientists led by Benoit Bruneau (left), including Irfan Kathiriya (center) and Kavitha Rao (right), make inroads into understanding what genes are improperly deployed in some cases of congenital heart disease.  Photo courtesy Gladstone Institute

For more than 20 years Dr. Benoit Bruneau has been trying to identify the causes of congenital heart disease, the most common form of birth defect in the U.S. It turns out that it’s not one cause, but many.

Congenital heart disease covers a broad range of defects, some relatively minor and others life-threatening and even fatal. It’s been known that a mutation in a gene called TBX5 is responsible for some of these defects, so, in a CIRM-funded study ($1.56 million), Bruneau zeroed in on this mutation to see if it could help provide some answers.

In the past Bruneau, the director of the Gladstone Institute of Cardiovascular Disease, had worked with a mouse model of TBX5, but this time he used human induced pluripotent stem cells (iPSCs). These are cells that can be manipulated in the lab to become any kind of cell in the human body. In a news release Bruneau says this was an important step forward.

“This is really the first time we’ve been able to study this genetic mutation in a human context. The mouse heart is a good proxy for the human heart, but it’s not exactly the same, so it’s important to be able to carry out these experiments in human cells.”

The team took some iPSCs, changed them into heart cells, and used a gene editing tool called CRISPR-Cas9 to create the kinds of mutations in TBX5 that are seen in people with congenital heart disease. What they found was some genes were affected a lot, some not so much. Which is what you might expect in a condition that causes so many different forms of problems.

“It makes sense that some are more affected than others, but this is the first experimental data in human cells to show that diversity,” says Bruneau.

But they didn’t stop there. Oh no. Then they did a deep dive analysis to understand how the different ways that different cells were impacted related to each other. They found some cells were directly affected by the TBX5 mutation but others were indirectly affected.

The study doesn’t point to a simple way of treating congenital heart disease but Bruneau says it does give us a much better understanding of what’s going wrong, and perhaps will give us better ideas on how to stop that.

“Our new data reveal that the genes are really all part of one network—complex but singular—which needs to stay balanced during heart development. That means if we can figure out a balancing factor that keeps this network functioning, we might be able to help prevent congenital heart defects.”

The study is published in the journal Developmental Cell.

CIRM-funded study discovers potential therapy for one of the leading causes of heart disease

Dr. Deepak Srivastava and his team found a drug candidate that could help prevent tens of thousands of heart surgeries every year. Image Credit: Gladstones Institute

According to the Center for Disease Control and Prevention (CDC), heart disease is the leading cause of death for men, women, and people of most racial and ethnic groups in the United States. About 655,000 Americans die from heart disease each year, which is about one in every four deaths.

Calcific aortic valve disease, the third leading cause of heart disease overall, occurs when calcium starts to accumulate in the heart valves and vessels over time, causing them to gradually harden like bone. This leads to obstruction of blood flow out of the heart’s pumping chamber, causing heart failure. Unfortunately there is no treatment for this condition, leaving patients only with the option of surgery to replace the heart valve once the hardening is severe enough.

But thanks to a CIRM-funded ($2.4 million) study conducted by Dr. Deepak Srivastava and his team at the Gladstone Institutes, a potential drug candidate for heart valve disease was discovered. It has been found to function in both human cells and animals and is ready to move toward a clinical trial.

For this study, Dr. Srivastava and his team looked for drug-like molecules that had the potential to correct the mechanism in heart valve disease that leads to gradual hardening. To do so, the team first had to determine the network of genes that are turned on or off in the diseased cells.

Once the genes were identified, they used an artificial intelligence method to train a machine learning program to detect whether a cell was healthy or diseased based on the network of genes identified. They proceeded to treat the diseased human cells with nearly 1,600 molecules in order to identify any drugs that would cause the machine learning program to reclassify diseased cells as healthy. The team successfully identified a few molecules that could correct diseased cells back to a healthy state.

Dr. Srivastara then collaborated with Dr. Anna Malashicheva, from the Russian Academy of Sciences, who had collected valve cells from over 20 patients at the time of surgical replacement. Using the valve cells that Dr. Malashicheva had collected, Dr. Srivastara and his team conducted a “clinical trial in a dish” in which they tested the molecules they had previously identified in the cells from the 20 patients with aortic valve hardening. The results were remarkable, as the molecule that seemed most effective in the initial study was able to restore these patients’ cells as well.

The final step taken was to determine whether the drug-like molecule would actually work in a whole, living organ. To do this, Dr. Srivastava and his team did a “pre-clinical trial” in a mouse model of the disease. The team found that the therapeutic candidate could successfully prevent and treat aortic valve disease. In young mice who had not yet developed the disease, the therapy prevented the hardening of the valve. In mice that already had the disease, the therapy was able to halt the disease and, in some cases, reverse it. This finding is especially important since most patients aren’t diagnosed until hardening of the heart valve has already begun.

Dr. Deepak Srivastava (left) and Dr. Christina V. Theodoris (right)
Image Credit: Gladstones Institute

Dr. Christina V. Theodoris, a lead author of the study who is now completing her residency in pediatric genetics, was a graduate student in Dr. Srivastava’s lab and played a critical role in this research. Her first project was to convert the cells from patient families into induced pluripotent stem cells (iPSCs), which have the potential of becoming any cell in the body. The newly created iPSCs were then turned into cells that line the valve, allowing the team to understand why the disease occurs. Her second project was to make a mouse model of calcific aortic valve disease, which enabled them to start using the models to identify a therapy.

In a press release from Gladstone Institutes, Dr. Theodoris, discusses the impact of the team’s research.

“Our strategy to identify gene network–correcting therapies that treat the core disease mechanism may represent a compelling path for drug discovery in a range of other human diseases. Many therapeutics found in the lab don’t translate well to humans or focus only on a specific symptom. We hope our approach can offer a new direction that could increase the likelihood of candidate therapies being effective in patients.”

In the same press release, Dr. Srivastava emphasizes the scientific advances that have driven the team’s research to this critical point.

“Our study is a really good example of how modern technologies are facilitating the kinds of discoveries that are possible today, but weren’t not so long ago. Using human iPSCs and gene editing allowed us to create a large number of cells that are relevant to the disease process, while powerful machine learning algorithms helped us identify, in a non-biased fashion, the important genes for distinguishing between healthy and diseased cells.”

The full results of this study were published in Science.

You can’t take it if you don’t make it

Biomedical specialist Mamadou Dialio at work in the Cedars-Sinai Biomanufacturing Center. Photo by Cedars-Sinai.

Following the race to develop a vaccine for COVID-19 has been a crash course in learning how complicated creating a new therapy is. It’s not just the science involved, but the logistics. Coming up with a vaccine that is both safe and effective is difficult enough, but then how do you make enough doses of it to treat hundreds of millions of people around the world?

That’s a familiar problem for stem cell researchers. As they develop their products they are often able to make enough cells in their own labs. But as they move into clinical trials where they are testing those cells in more and more people, they need to find a new way to make more cells. And, of course, they need to plan ahead, hoping the therapy is approved by the Food and Drug Administration, so they will need to be able to manufacture enough doses to meet the increased demand.

We saw proof of that planning ahead this week with the news that Cedars-Sinai Medical Center in Los Angeles has opened up a new Biomanufacturing Center.

Dr. Clive Svendsen, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, said in a news release, the Center will manufacture the next generation of drugs and regenerative medicine therapies.

“The Cedars-Sinai Biomanufacturing Center leverages our world-class stem-cell expertise, which already serves scores of clients, to provide a much-needed biomanufacturing facility in Southern California. It is revolutionary by virtue of elevating regenerative medicine and its therapeutic possibilities to an entirely new level-repairing the human body.”

This is no ordinary manufacturing plant. The Center features nine “clean rooms” that are kept free from dust and other contaminants. Everyone working there has to wear protective suits and masks to ensure they don’t bring anything into the clean rooms.

The Center will specialize in manufacturing induced pluripotent stem cells, or iPSCs. Dhruv Sareen, PhD, executive director of the Biolmanufacturing Center, says iPSCs are cells that can be turned into any other kind of cell in the body.

“IPSCs are powerful tools for understanding human disease and developing therapies. These cells enable us to truly practice precision medicine by developing drug treatments tailored to the individual patient or groups of patients with similar genetic profiles.”

The Biomanufacturing Center is designed to address a critical bottleneck in bringing cell- and gene-based therapies to the clinic. After all, developing a therapy is great, but it’s only half the job. Making enough of it to help the people who need it is the other half.

CIRM is funding Dr. Svendsen’s work in developing therapies for ALS and other diseases and disorders.  

CIRM-funded development of stem cell therapy for Canavan disease shows promising results

Yanhong Shi, Ph.D., City of Hope

Canavan disease is a fatal neurological disorder, the most prevalent form of which begins in infancy. It is caused by mutation of the ASPA gene, resulting in the deterioration of white matter (myelin) in the brain and preventing the proper transmission of nerve signals.  The mutated ASPA gene causes the buildup of an amino acid called NAA and is typically found in neurons in the brain.  As a result of the NAA buildup, Canavan disease causes symptoms such as impaired motor function, mental retardation, and early death. Currently, there is no cure or standard of treatment for this condition.

Fortunately, CIRM-funded research conducted at City of Hope by Yanhong Shi, Ph.D. is developing a stem cell-based treatment for Canavan disease. The research is part of CIRM’s Translational Stage Research Program, which promotes the activities necessary for advancement to clinical study of a potential therapy.

The results from the study are promising, with the therapy improving motor function, reducing degeneration of various brain regions, and expanding lifespan in a Canavan disease mouse model.

For this study, induced pluripotent stem cells (iPSCs), which can turn into virtually any type of cells, were created from skin cells of Canavan disease patients. The newly created iPSCs were then used to create neural progenitor cells (NPCs), which have the ability to turn into various types of neural cells in the central nervous system. A functional version of the ASPA gene was then introduced into the NPCs. These newly created NPCs were then transplanted inside the brains of Canavan disease mice.

The study also used iPSCs engineered to have a functional version of the ASPA gene. The genetically modified iPSCs were then used to create oligodendrocyte progenitor cells (OPCs), which have the ability to turn into myelin. The OPCs were also transplanted inside the brains of mice.

The rationale for evaluating both NPCs and OPCs was that NPCs typically stayed at the site of injection while OPCs tend to migrate, which might have been important in terms of the effectiveness of the therapy.  However, the results of the study show that both NPCs and OPCs were effective, with both being able to reduce levels of NAA, presumably because NAA can move to where the ASPA enzyme is although NPCs do not migrate.  This resulted in improved motor function, recovery of myelin, and reduction of brain degeneration, in both the NPC and OPC-transplanted Canavan disease mice.

“Thanks to funding from CIRM and the hard work of my team here at City of Hope and collaborators at Center for Biomedicine and Genetics, Department of Molecular Imaging and Therapy, and Diabetes and Metabolism Institute at City of Hope, as well as collaborators from the University of Texas Medical Branch at Galveston, University of Rochester Medical Center, and Aarhus University, we were able to carry out this study which has demonstrated promising results,” said Dr. Shi.  “I hope that these findings can one day bring about an effective therapy for Canavan disease patients, who currently have no treatment options.”

Dr. Shi and her team will build on this research by starting IND-enabling studies using their NPC therapy soon.  This is the final step in securing approval from the Food and Drug Administration (FDA) in order to test the therapy in patients.  

The full study was published in Advanced Science.

Cures, clinical trials and unmet medical needs

When you have a great story to tell there’s no shame in repeating it as often as you can. After all, not everyone gets to hear first time around. Or second or third time. So that’s why we wanted to give you another opportunity to tune into some of the great presentations and discussions at our recent CIRM Alpha Stem Cell Clinic Network Symposium.

It was a day of fascinating science, heart-warming, and heart-breaking, stories. A day to celebrate the progress being made and to discuss the challenges that still lie ahead.

There is a wide selection of topics from “Driving Towards a Cure” – which looks at some pioneering work being done in research targeting type 1 diabetes and HIV/AIDS – to Cancer Clinical Trials, that looks at therapies for multiple myeloma, brain cancer and leukemia.

The COVID-19 pandemic also proved the background for two detailed discussions on our funding for projects targeting the coronavirus, and for how the lessons learned from the pandemic can help us be more responsive to the needs of underserved communities.

Here’s the agenda for the day and with each topic there’s a link to the video of the presentation and conversation.

Thursday October 8, 2020

View Recording: CIRM Fellows Trainees

9:00am Welcome Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director  

Catriona Jamieson, MD,  View Recording: ASCC Network Value Proposition

9:10am Session I:  Cures for Rare Diseases Innovation in Action 

Moderator: Mark Walters, MD, UCSF, ASCC Program Director 

Don Kohn, MD, UCLA – View Recording: Severe combined immunodeficiency (SCID) 

Mark Walters, MD, UCSF, ASCC Program Director – View Recording: Thalassemia 

Pawash Priyank, View Recording: Patient Experience – SCID

Olivia and Stacy Stahl, View Recording: Patient Experience – Thalassemia

10 minute panel discussion/Q&A 

BREAK

9:55am Session II: Addressing Unmet Medical Needs: Driving Towards a Cure 

Moderator: John Zaia, MD, City of Hope, ASCC Program Direction 

Mehrdad Abedi, MD, UC Davis Health, ASCC Program Director – View Recording: HIV

Manasi Jaiman, MD, MPH, ViaCyte, Vice President, Clinical Development – View Recording: Diabetes

Jeff Taylor, Patient Experience – HIV

10 minute panel discussion/Q&A 

BREAK

10:40am Session III: Cancer Clinical Trials: Networking for Impact 

Moderator: Catriona Jamieson, MD, UC San Diego, ASCC Program Director 

Daniela Bota, MD, PhD, UC Irvine, ASCC Program Director – View Recording:  Glioblastoma 

Michael Choi, MD, UC San Diego – View Recording: Cirmtuzimab

Matthew Spear, MD, Poseida Therapeutics, Chief Medical Officer – View Recording: Multiple Myeloma  

John Lapham, Patient Experience –  View Recording: Chronic lymphocytic leukemia (CLL) 

10 minute panel discussion/Q&A 

BREAK

11:30am Session IV: Responding to COVID-19 and Engaging Communities

Two live “roundtable conversation” sessions, 1 hour each.

Roundtable 1: Moderator Maria Millan, MD, CIRM 

CIRM’s / ASCC Network’s response to COVID-19 Convalescent Plasma, Cell Therapy and Novel Vaccine Approaches

Panelists

Michael Matthay, MD, UC San Francisco: ARDS Program

Rachael Callcut, MD, MSPH, FACS, UC Davis: ARDS Program 

John Zaia, MD, City of Hope: Convalescent Plasma Program 

Daniela Bota, MD, PhD, UC Irvine: Natural Killer Cells as a Treatment Strategy 

Key questions for panelists: 

  • Describe your trial or clinical program?
  • What steps did you take to provide access to disproportionately impacted communities?
  • How is it part of the overall scientific response to COVID-19? 
  • How has the ASCC Network infrastructure accelerated this response? 

Brief Break

Roundtable 2: Moderator Ysabel Duron, The Latino Cancer Institute and Latinas Contra Cancer

View Recording: Roundtable 2

Community Engagement and Lessons Learned from the COVID Programs.  

Panelists

Marsha Treadwell, PhD, UC San Francisco: Community Engagement  

Sheila Young, MD, Charles R. Drew University of Medicine and Science: Convalescent Plasma Program in the community

David Lo, MD, PhD,  UC Riverside: Bringing a public health perspective to clinical interventions

Key questions for panelists: 

  • What were important lessons learned from the COVID programs? 
  • How can CIRM and the ASCC Network achieve equipoise among communities and engender trust in clinical research? 
  • How can CIRM and the ASCC Network address structural barriers (e.g. job constrains, geographic access) that limit opportunities to participate in clinical trials?

Partners in health

From left to right: Heather Dahlenburg, Jan Nolta, Jeannine Logan White, Sheng Yang
From left to right: Heather Dahlenburg, staff research associate; Jan Nolta, director of the Stem Cell Program; Jeannine Logan White, advanced cell therapy project manager; Sheng Yang, graduate student, Bridges Program, Humboldt State University, October 18, 2019. (AJ Cheline/UC Davis)

At CIRM we are modest enough to know that we can’t do everything by ourselves. To succeed we need partners. And in UC Davis we have a terrific partner. The work they do in advancing stem cell research is exciting and really promising. But it’s not just the science that makes them so special. It’s also their compassion and commitment to caring for patients.

What follows is an excerpt from an article by Lisa Howard on the work they do at UC Davis. When you read it you’ll see why we are honored to be a part of this research.

Gene therapy research at UC Davis

UC Davis’ commitment to stem cell and gene therapy research dates back more than a decade.

In 2010, with major support from the California Institute for Regenerative Medicine (CIRM), UC Davis launched the UC Davis Institute for Regenerative Cures, which includes research facilities as well as a Good Manufacturing Practice (GMP) facility.

In 2016, led by Fred Meyers, a professor in the School of Medicine, UC Davis launched the Center for Precision Medicine and Data Sciences, bringing together innovations such as genomics and biomedical data sciences to create individualized treatments for patients.

Last year, the university launched the Gene Therapy Center, part of the IMPACT Center program.

Led by Jan Nolta, a professor of cell biology and human anatomy and the director of the UC Davis Institute for Regenerative Cures, the new center leverages UC Davis’ network of expert researchers, facilities and equipment to establish a center of excellence aimed at developing lifelong cures for diseases.

Nolta began her career at the University of Southern California working with Donald B. Kohn on a cure for bubble baby disease, a condition in which babies are born without an immune system. The blood stem cell gene therapy has cured more than 50 babies to date.

Work at the UC Davis Gene Therapy Center targets disorders that potentially can be treated through gene replacement, editing or augmentation.

“The sectors that make up the core of our center stretch out across campus,” said Nolta. “We work with the MIND Institute a lot. We work with the bioengineering and genetics departments, and with the Cancer Center and the Center for Precision Medicine and Data Sciences.”

A recent UC Davis stem cell study shows a potential breakthrough for healing diabetic foot ulcers with a bioengineered scaffold made up of human mesenchymal stem cells (MSCs). Another recent study revealed that blocking an enzyme linked with inflammation enables stem cells to repair damaged heart tissue. A cell gene therapy study demonstrated restored enzyme activity in Tay-Sachs disease affected cells in humanized mouse models.

Several cell and gene therapies have progressed to the point that ongoing clinical trials are being conducted at UC Davis for diseases, including sickle-cell anemia, retinopathy, muscle injury, dysphasia, advanced cancer, and Duchenne muscular dystrophy, among others.

“Some promising and exciting research right now at the Gene Therapy Center comes from work with hematopoietic stem cells and with viral vector delivery,” said Nolta.

Hematopoietic stem cells give rise to other blood cells. A multi-institutional Phase I clinical trial using hematopoietic stem cells to treat HIV-lymphoma patients is currently underway at UC Davis.

.Joseph Anderson

Joseph Anderson

“We are genetically engineering a patient’s own blood stem cells with genes that block HIV infection,” said Joseph Anderson, an associate professor in the UC Davis Department of Internal Medicine. The clinical trial is a collaboration with Mehrdad Abedi, the lead principal investigator.

“When the patients receive the modified stem cells, any new immune system cell, like T-cell or macrophage, that is derived from one of these stem cells, will contain the HIV-resistant genes and block further infection,” said Anderson.

He explained that an added benefit with the unique therapy is that it contains an additional gene that “tags” the stem cells. “We are able to purify the HIV-resistant cells prior to transplantation, thus enriching for a more protective cell population.

Kyle David Fink

Kyle David Fink

Kyle David Fink, an assistant professor of neurology at UC Davis, is affiliated with the Stem Cell Program and Institute for Regenerative Cures. His lab is focused on leveraging institutional expertise to bring curative therapies to rare, genetically linked neurological disorders.

“We are developing novel therapeutics targeted to the underlying genetic condition for diseases such as CDKL5 deficiency disorder, Angelman, Jordan and Rett syndromes, and Juvenile Huntington’s disease,” said Fink.

The lab is developing therapies to target the underlying genetic condition using DNA-binding domains to modify gene expression in therapeutically relevant ways. They are also creating novel delivery platforms to allow these therapeutics to reach their intended target: the brain.

“The hope is that these highly innovative methods will speed up the progress of bringing therapies to these rare neurodegenerative disease communities,” said Fink.Jasmine Carter, a graduate research assistant at the UC Davis Stem Cell Program.

Jasmine Carter, a graduate research assistant at the UC Davis Stem Cell Program, October 18, 2019. (AJ Cheline/UC Davis)

Developing potential lifetime cures

Among Nolta’s concerns is how expensive gene therapy treatments can be.

“Some of the therapies cost half a million dollars and that’s simply not available to everyone. If you are someone with no insurance or someone on Medicare, which reimburses about 65 percent, it’s harder for you to get these life-saving therapies,” said Nolta.

To help address that for cancer patients at UC Davis, Nolta has set up a team known as the “CAR T Team.”

Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy in which a patient’s own immune cells are reprogrammed to attack a specific protein found in cancer cells.

“We can develop our own homegrown CAR T-cells,” said Nolta. “We can use our own good manufacturing facility to genetically engineer treatments specifically for our UC Davis patients.”

Although safely developing stem cell treatments can be painfully slow for patients and their families hoping for cures, Nolta sees progress every day. She envisions a time when gene therapy treatments are no longer considered experimental and doctors will simply be able to prescribe them to their patients.

“And the beauty of the therapy is that it can work for the lifetime of a patient,” said Nolta.

Exploring tough questions, looking for answers

COVID-19 and social and racial injustice are two of the biggest challenges facing the US right now. This Thursday, October 8th, we are holding a conversation that explores finding answers to both.

The CIRM Alpha Stem Cell Clinic Network Symposium is going to feature presentations about advances in stem cell and regenerative research, highlighting treatments that are already in the clinic and being offered to patients.

But we’re also going to dive a little deeper into the work we support, and use it to discuss two of the most pressing issues of the day.

One of the topics being featured is research into COVID-19. To date CIRM has funded 17 different projects, including three clinical trials. We’ll talk about how these are trying to find ways to help people infected with the virus, seeing if stem cells can help restore function to organs and tissues damaged by the virus, and if we can use stem cells to help develop safe and effective vaccines.

Immediately after that we are going to use COVID-19 as a way of exploring how the people most at risk of being infected and suffering serious consequences, are also the ones most likely to be left out of the research and have most trouble accessing treatments and vaccines.

Study after study highlights how racial and ethnic minorities are underrepresented in clinical trials and disproportionately affected by debilitating diseases. We have a responsibility to change that, to ensure that the underserved are given the same opportunity to take part in clinical trials as other communities.

How do we do that, how do we change a system that has resisted change for so long, how do we overcome the mistrust that has built up in underserved communities following decades of abuse? We’ll be talking about with experts who are on the front lines of this movement.

It promises to be a lively meeting. We’d love to see you there. It’s virtual – of course – it’s open to everyone, and it’s free.

Here’s where you can register and find out more about the Symposium

CIRM Bridges program prepared student for research of a rare disease

Ian Blong, Ph.D., CIRM San Francisco State University Bridges to Stem Cell Research Alumnus

Recently, The New York Times released a powerful article that tells the stories of four different families navigating the challenges of having a family member with a rare disease. One of these stories focused on Matt Wilsey, a tech entrepreneur and investor in California’s Silicon Valley, and his daughter Grace, who was born with an extremely rare genetic disorder named NGLY1 deficiency. This genetic disorder causes developmental delay, intellectual disability, seizures, and other movement issues.

Matt and Kristen Wilsey with their 10-year-old daughter Grace, who has a rare genetic disorder, at the Grace Science headquarters in Menlo Park, Calif.
Image Credit: James Tensuan for The New York Times

Matt decided to put his entrepreneurial and networking skills to good use in order to form Grace Science Foundation, an organization whose focus is to pioneer approaches to scientific discovery in order to develop a cure for NGLY1 deficiency. One researcher that Matt brought on board was Carolyn Bertozzi, Ph.D., a chemist from Stanford University. A graduate student in her laboratory, Ian Blong, Ph.D., decided to study NGLY1 and was able to complete his dissertation while working on this topic at Stanford University.

Ian’s journey towards obtaining his Ph.D. started after being accepted into the San Francisco State University (SFSU) CIRM Bridges to Stem Cell Research Master’s Program. CIRM funding for this program allowed students like Ian to take courses at SFSU while also working in labs at world renown institutions in the Bay Area such as UCSF, Stanford, and UC Berkeley.

Carolyn Bertozzi, Ph.D.
Image Credit: L.A. Cicero

In exploring the various options afforded to him by the CIRM, Ian found Dr. Bertozzi’s lab at UC Berkeley, where he focused on early stage discovery research. His master’s thesis project focused on how to generate rare neuronal and and neural crest cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Both of these stem cell types can generate virtually any kind of cell, but iPSCs are unique in that they can be generated from the adult cells (such as skin) of a patient.

Ian decided to continue his studies in Dr. Bertozzi’s lab by continuing his research in a Ph.D. program at UC Berkeley. He credits the SFSU CIRM Bridges Program with giving him the opportunity to work under a prestigious PI and in her lab at UC Berkeley, which allowed him to continue his studies there.

“The CIRM Bridges Program gave me the confidence and resources to pursue my dreams. Being able to have the capability of going to Berkeley and do research with top tier scientists along with the support from CIRM. Without CIRM, I wouldn’t have had the courage to go to those universities to get my foot in the door.”

Eventually, Dr. Bertozzi move her operations to Stanford University and Ian continued his Ph.D. studies there. Stanford provided him the opportunity to focus more on the translational stage, which is an area of research aimed at developing a therapeutic candidate. Going into his Ph.D. work, Ian was able to build upon his previous “discovery stage” knowledge of generating neuronal and neural crest cells from iPSCS and hESCs.

An area of his work at Stanford focused on generating neural crest cells from iPSCs of those with NGLY1 deficiency. The goal was to identify a phenotype, which is an observable characteristic such as physical form. Identifying this would help better understand potential differentiation pathways that underlie NGLY1 deficiency, which could lead to the development a potential treatment for the condition.

Flash forward to present day and Ian is still using the knowledge he learned from his time in the SFSU CIRM Bridges to Stem Cell Research Program. He is currently a scientist at the healthcare company Roche, where his focus is on manufacturing future diagnostics and therapeutics on a much larger scale, a complex and extremely critical process necessary in widely distributing potential stem cell-based treatments.

Ian’s experience and opportunities provided to him is just one of the many examples of how the various CIRM Bridges Programs across California have given students the resources needed to become the next generation of scientists.