How the Tooth Fairy is helping unlock the secrets of autism

Our 2021-22 Annual Report is now online. It’s filled with information about the work we have done over the last year (we are on a fiscal calendar year from July 1 – June 30), the people who have helped us do that work, and some of the people who have benefited from that work. One of those is Dr. Alysson Muotri, a professor in the Departments of Pediatrics and Cellular & Molecular Medicine at the University of California, San Diego.

Dr. Alysson Muotri, in his lab at UCSD

For Dr. Alysson Muotri, trying to unlock the secrets of the brain isn’t just a matter of scientific curiosity, it’s personal. He has a son with autism and Dr. Muotri is looking for ways to help him, and millions of others like him around the world.

He created the Tooth Fairy project where parents donated more than 3,000 baby teeth from  children with autism and children who are developing normally. Dr. Muotri then turned cells from those teeth into neurons, the kind of brain cell affected by autism. He is using those cells to try and identify how the brain of a child with autism differs from a child who is developing normally.

“We’ve been using cells from this population to see what are the alterations (in the gene) and if we can revert them back to a normal state. If you know the gene that is affected, and autism has a strong genetic component, by genome sequencing you can actually find what are the genes that are affected and in some cases there are good candidates for gene therapy. So, you just put the gene back. And we can see that in the lab where we are correcting the gene that is mutated, the networks start to function in a way that is more neurotypical or normal. We see that as highly promising, there’s a huge potential here to help those individuals.”

He is also creating brain organoids, three-dimensional structures created from stem cells that mimic some of the actions and activities of the brain. Because these are made from human cells, not mice or other animals, they may be better at indicating if new therapies have any potential risks for people.

“We can test drugs in the brain organoids of the person and see if it works, see if there’s any toxicity before you actually give the drug to a person, and it will save us time and money and will increase our knowledge about the human brain.”

He says he still gets excited seeing how these cells work. “It’s amazing, it’s a miracle. Every time I see it, it’s like seeing dolphins in the sea because it’s so beautiful.”

Dr. Muotri is also a big proponent of diversity, equity and inclusion in scientific research. He says in the past it was very much a top-down model with scientists deciding what was important. He says we need to change that and give patients and communities a bigger role in shaping the direction of research.

“I think this is something we scientists have to learn, how to incorporate patients in our research. These communities are the ones we are studying, and we need to know what they want and not assume that what we want is what they want. They should be consulted on our grants, and they should participate in the design of our experiments. That is the future.”

So far, some encouraging news for stem cell clinical trial treating epilepsy

Neurona Therapeutics is testing a new therapy for a drug-resistant form of epilepsy and has just released some encouraging early findings. The first patient treated went from having more than 30 seizures a month to just four seizures over a three-month period.

This clinical trial, funded by the California Institute for Regenerative Medicine (CIRM), is targeting  mesial temporal lobe epilepsy (MTLE), one of the most common forms of epilepsy. Because the seizures caused by MTLE are frequent, they can be particularly debilitating and increase the risk of a decreased quality of life, depression, anxiety and memory impairment.

Neurona’s therapy, called NRTX-1001, consists of a specialized type of neuronal cell derived from embryonic stem cells.  Neuronal cells are messenger cells that transmit information between different areas of the brain, and between the brain and the rest of the nervous system.

NRTX-1001 is injected into the brain in the area affected by the seizures where it releases neurotransmitters or chemical messengers that will block the signals in the brain causing the epileptic seizures.

The first patient treated had a nine-year history of epilepsy and, despite being on anti-epileptic medications, was experiencing dozens of seizures a month. Since the therapy he has had only four seizures in three months. The therapy hasn’t produced any serious side effects.

In a news release Dr. Cory Nicholas, Neurona’s President and CEO, said while this is only one patient, it’s good news.

“The reduced number of seizures reported by the first person to receive NRTX-1001 is very encouraging, and we remain cautiously optimistic that this reduction in seizure frequency will continue and extend to others entering this cell therapy trial. NRTX-1001 administration has been well tolerated thus far in the clinic, which is in line with the extensive preclinical safety data collected by the Neurona team. With recent clearance from the Data Safety Monitoring Board we are excited to continue patient enrollment. We are very grateful to these first participants, and thank the clinical teams for the careful execution of this pioneering study.”

CIRM has been a big supporter of this work from the early Discovery stage work to this clinical trial. That’s because when we find something promising, we want to do everything we can to help it live up to its promise.

Join Us on Stem Cell Awareness Day (October 12)!

In 2004, the California Institute for Regenerative Medicine (CIRM) was created by the people of California to accelerate stem cell treatments to patients with unmet medical needs.  
 
Since then, we’ve expanded our mission to accelerate world class science for California and the world. We’ve funded and supported a pipeline of medical research from initial scientific discovery to development and testing. We also remain committed to training the next generation of regenerative medicine scientists to research cutting edge therapies for patients.  
 
We’ve achieved a lot but recognize there’s still lots more work to be done. That’s why we’re inviting everyone to join us for a virtual webinar on October 12th for Stem Cell Awareness Day, a day when we mark the progress being made in regenerative medicine, stem cell and gene therapy research. 
 
This Stem Cell Awareness Day, the CIRM team will highlight our achievements in research, clinical trials and education. We will also look ahead to explore how we can best further our mission. 
 
Speakers will include: 
Jonathan Thomas — Chair, CIRM Board  
Dr. Kelly Shepard — Associate Director, Scientific Programs 
Dr. Lisa Kadyk — Associate Director, Therapeutics Development 
Dr. Mitra Hooshmand — Sr. Science Officer, Special Projects & Strategic Initiatives 
 
The event is free and you can register here. If you have a question you would like to ask the team, please email them to info@cirm.ca.gov ahead of time. We will do our best to answer all questions during the webinar and those we can’t get to we’ll answer The Stem Cellar.  
 
We look forward to seeing you there! 

Funding a Clinical Trial for a Functional Cure for HIV

The use of antiretroviral drugs has turned HIV/AIDS from a fatal disease to one that can, in many cases in the US, be controlled. But these drugs are not a cure. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) voted to approve investing $6.85 million in a therapy that aims to cure the disease.

This is the 82nd clinical trial funded by CIRM.

There are approximately 38 million people worldwide living with HIV/AIDS. And each year there are an estimated 1.5 million new cases. The vast majority of those living with HIV do not have access to the life-saving antiretroviral medications that can keep the virus under control. People who do have access to the medications face long-term complications from them including heart disease, bone, liver and kidney problems, and changes in metabolism.

The antiretroviral medications are effective at reducing the viral load in people with HIV, but they don’t eliminate it. That’s because the virus that causes AIDS can integrate its DNA into long-living cells in the body and remain dormant. When people stop taking their medications the virus is able to rekindle and spread throughout the body.

Dr. William Kennedy and the team at Excision Bio Therapeutics have developed a therapeutic candidate called EBT-101. This is the first clinical study using the CRISPR-based platform for genome editing and excision of the latent form of HIV-1, the most common form of the virus that causes AIDS in the US and Europe. The goal is to eliminate or sufficiently reduce the hidden reservoirs of virus in the body to the point where the individual is effectively cured.

“To date only a handful of people have been cured of HIV/AIDS, so this proposal of using gene editing to eliminate the virus could be transformative,” says Dr. Maria Millan, President and CEO of CIRM. “In California alone there are almost 140,000 people living with HIV. HIV infection continues to disproportionately impact marginalized populations, many of whom are unable to access the medications that keep the virus under control. A functional cure for HIV would have an enormous impact on these communities, and others around the world.”

In a news release announcing they had dosed the first patient, Daniel Dornbusch, CEO of Excision, called it a landmark moment. “It is the first time a CRISPR-based therapy targeting an infectious disease has been administered to a patient and is expected to enable the first ever clinical assessment of a multiplexed, in vivo gene editing approach. We were able to reach this watershed moment thanks to years of innovative work by leading scientists and physicians, to whom we are immensely grateful. With this achievement, Excision has taken a major step forward in developing a one-time treatment that could transform the HIV pandemic by freeing affected people from life-long disease management and the stigma of disease.”

The Excision Bio Therapeutics team also scored high on their plan for Diversity, Equity and Inclusion. Reviewers praised them for adding on a partnering organization to provide commitments to serve underserved populations, and to engaging a community advisory board to help guide their patient recruitment.

CIRM has already invested almost $81 million in 20 projects targeting HIV/AIDS, including four clinical trials.

Fast Track Designation for a therapy making transplants safer for children with a fatal immune disorder

Bone marrow transplant

For children born with severe combined immunodeficiency (SCID) life can be very challenging. SCID means they have no functioning immune system, so even a simple infection can prove life threatening. Left untreated, children with SCID often die in the first few years of life.

There are stem cell/gene therapies funded by the California Institute for Regenerative Medicine (CIRM), such as ones at UCLA and UCSF/St. Judes, but an alternative method of treating, and even curing the condition, is a bone marrow or hematopoietic stem cell transplant (HCT). This replaces the child’s blood supply with one that is free of the SCID mutation, which helps restore their immune system.

However, current HCT methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.

To change that, Dr. Judy Shizuru at Stanford University, with CIRM funding, developed an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells, creating the room needed to transplant new, healthy cells. The goal was to make stem cell transplants safer and more effective for the treatment of many life-threatening blood disorders.

That approach, JSP191, is now being championed by Jasper Therapeutics and they just got some very good news from the Food and Drug Administration (FDA). The FDA has granted JSP191 Fast Track Designation, which can speed up the review of therapies designed to treat serious conditions and fill unmet medical needs.

In a news release, Ronald Martell, President and CEO of Jasper Therapeutics, said this is good news for the company and patients: “This new Fast Track designation recognizes the potential role of JSP191 in improving clinical outcomes for these patients and will allow us to more closely work with the FDA in the upcoming months to determine a path toward a Biologics License Application (BLA) submission.”

Getting a BLA means Jasper will be able to market the antibody in the US and make it available to all those who need it.

This is the third boost from the FDA for Jasper. Previously the agency granted JSP191 both Orphan and Rare Pediatric Disease designations. Orphan drug designation qualifies sponsors for incentives such as tax credits for clinical trials. Rare Pediatric Disease designation means that if the FDA does eventually approve JSP191, then Jasper can apply to receive a priority review of an application to use the product for a different disease, such as someone who is getting a bone marrow transplant for sickle cell disease or severe auto immune diseases.

A pioneering couple uproot their lives to help their baby

Our 2021-22 Annual Report is now online. It’s filled with information about the work we have done over the last year (we are on a fiscal calendar year from July 1 – June 30), the people who have helped us do that work, and some of the people who have benefited from that work. We start our look at some of the stories in the Annual Report with Michelle, Jeff and Toby.

Michelle, Jeff and baby Toby

When Michelle Johnson and Jeff Maginnis learned they were expecting a baby they were elated. Then an ultrasound exam at 20 weeks into the pregnancy showed the fetus had spina bifida, a birth defect that occurs when the spine and spinal cord don’t form properly. Spina bifida can result in life-long walking and mobility problems for the child, even paralysis.

The couple were referred to UC Davis where Dr. Diana Farmer and Dr. Aijun Wang were running a clinical trial, funded by CIRM, using stem cells, taken from a donor placenta. The cells were seeded onto a synthetic scaffold which was then placed over the injury site in the womb. Tests in animals show this approach was able to repair the defect and prevent paralysis. Michelle was going to be just the second woman to see if this approach also worked in people.

For the couple, it wasn’t an easy decision. They had just bought a house and hadn’t even moved in. Michelle said they had to work quickly.

“It was a tough 3 – 5 days, a lot of research, a lot of soul searching trying to figure out what to do. I had always heard that stem cells were the medicine of the future and so I said ‘wow, this is amazing, we have to do this.’ That meant moving down here (to Sacramento from Portland, Oregon), having to relocate till Toby was born. When they approved us for the trial, it was like our prayers had been answered. The second person in the world. Our chances of winning the lottery were better!”

They got the keys to their new home the same day they flew down to Sacramento. The only thing they brought with them, was their dog.

Michelle said the surgery was challenging: “It’s really hard to heal from surgery when you have a child still growing at the incision site. That was hard.” But she says when the baby was born it was all worthwhile: “Holding him for the first time and it was like, I can’t believe we did this, we made it, we survived this crazy experience of surgery and just not knowing if this will even work. But then he’s born and he’s just so normal.”

They named their son Toby. Dad Jeff says three months in everything is looking promising, Toby is hitting all his milestones and wriggling his legs. They know that problems may not be evident until Toby tries to crawl and walk. But for now, they are happy.

And Michelle says Toby is too. “He is the happiest baby and I said I think everyone needs some stem cells, because he’s so happy all the time.”

A newfound passion for stem cell research

All her life, Madison Waterlander knew that she wanted to be a part of the medical field. But soon after graduating from the University of Hawaii with her undergraduate degree, the COVID-19 pandemic hit. It was during this time that she noticed how crucial biomedical research was in the medical field and lives of patients, and when she realized she had a passion for research.  

She soon after found a master’s program in biotechnology and bioinformatics at California State University Channel Islands (CI), just a few minutes from Camarillo, the town she grew up in.  

Looking further into the program, she learned that to pursue a Stem Cell Technology and Laboratory Management emphasis for the degree, she would have to complete a one-year lab internship funded by the California Institute for Regenerative Medicine (CIRM). The internship was part of CIRM’s Bridges to Stem Cell Research and Therapy Program, which prepares California undergraduate and master’s graduate students for highly productive careers in stem cell research and therapy development.  

The opportunity to have hands-on experience in a lab through the internship solidified her decision to join the graduate program. 

Once she settled into the program at CSU Channel Islands, she began her internship, which took place at UC Santa Barbara in the Weimbs Lab. While there, she researched the underlying mechanisms and possible new therapies for Autosomal Dominant Polycystic Kidney Disease (ADPKD), a genetic disorder characterized by the growth of numerous cysts in the kidneys.  

“This CIRM-funded internship was so enriching for me, and I was able to expand my knowledge and skill set immensely in the laboratory,” Madison says. “I always knew that I loved science and the medical field, but this experience truly helped me realize that my strongest passion resides in the scientific research that goes into improving the quality of patient care and treatments.” 

While Madison says the internship supported her knowledge in the lab and was an overall positive experience, she also faced some personal challenges during that time, including losing her grandma. She struggled with the loss, but Madison says her time in the lab allowed her to focus on something she loved doing and that her grandma always encouraged her to do. 

“My grandma never would have wanted me to give up, so that truly helped to push me to continue on, and to try my hardest in every day to make an impact,” Madison says. 

After a year of hard work in the lab, Madison officially graduated from CSU Channel Islands this summer with a Master of Science Degree in Biotechnology and Bioinformatics with a Stem Cell Technology and Laboratory Management emphasis. Now, Madison is pursuing a role in the biotechnology industry within translational biomedical research.

“I truly enjoyed every moment of my CIRM internship, and I feel that it truly revealed to me just how much I enjoy participating in biomedical research,” Madison says. “I’ve always felt that research feels like a treasure hunt looking for cures and treatments, so the more of us that are partaking in the treasure hunt, the quicker we can find new treatments and provide solutions for patients.” 

Stories like Madison’s are why CIRM remains committed to training the next generation of scientists to conduct research and deliver regenerative medicine and stem cell therapies to patients. To date, there are 1,663 Bridges alumni, and another 109 Bridges trainees—including Madison—who are completing their internships in 2022.   

The race to cure sickle cell disease

September is National Sickle Cell Awareness Month, a time to refocus our efforts to find new treatments, even a cure, for people with sickle cell disease. Until we get those, CIRM remains committed to doing everything we can to reduce the stigma and bias that surrounds it.

Sickle cell disease (SCD) is a rare, inherited blood disorder in which normally smooth and round red blood cells may become sickle-shaped and harden. These blood cells can clump together and clog up arteries, causing severe and unpredictable bouts of pain, organ damage, vision loss and blindness, strokes and premature death.

There is a cure, a bone marrow transplant from someone who is both a perfect match and doesn’t carry the SCD trait. However, few patients are able to find that perfect match and even if they do the procedure carries risks.

That’s why the California Institute for Regenerative Medicine (CIRM) has invested almost $60 million in 14 projects, including five clinical trials targeting the disease. It’s also why we are partnering with the National Heart, Lung and Blood Institute (NHLBI) in their Cure Sickle Cell Initiative (CureSCi).

As part of the events around National Sickle Cell Awareness Month the NHLBI is launching the Gene Therapy to Reduce All Sickle Pain (GRASP) Trial and hosting a special Journeys in Mental Health Webinar on September 27th

The GRASP Trial is a Phase 2 trial that will take place at various locations throughout the country.  It’s a collaboration between the NHLBI and CIRM. Researchers are testing whether a gene therapy approach can improve or eliminate sickle cell pain episodes.  

Shortly after being born, babies stop producing blood containing oxygen-rich fetal hemoglobin and instead produce blood with the adult hemoglobin protein. For children with sickle cell disease, the transition from the fetal to the adult form of hemoglobin marks the onset of anemia and the painful symptoms of the disorder.

Scientists previously discovered that the BCL11A gene helps to control fetal hemoglobin and that decreasing the expression of this gene can increase the amount of fetal hemoglobin while at the same time reducing the amount of sickle hemoglobin in blood.  This could result in boosting the production of normal shaped red blood cells with a goal of curing or reducing the severity of sickle cell disease.   

The approach used in this trial is similar to a bone marrow transplant, but instead of using donor stem cells, this uses the patient’s own blood stem cells with new genetic information that instructs red blood cells to silence the expression of the BCL11A gene. This approach is still being studied to make sure that it is safe and effective, but it potentially has the advantage of eliminating some of the risks of other therapies. 

In this trial, patients will have to spend some time in an inpatient unit as they undergo chemotherapy to kill some bone marrow blood stem cells and create room for the new, gene-modified cells to take root.

The trial is based on a successful pilot/phase 1 study which showed it to be both safe and effective in the initial 10 patients enrolled in the trial.

For more information about the trial, including inclusion/exclusion criteria and trial locations, please visit the CureSCi GRASP trial page.

Nancy Rene, a sickle cell disease patient advocate, says while clinical trials like this are obviously important, there’s another aspect of the treatment of people with the disease that is still too often overlooked.

“As much as I applaud CIRM for the work they are doing to find a therapy or cure for Sickle Cell, I am often dismayed by the huge gulf between research protocols and general medical practice. For every story I hear about promising research, there is often another sad tale about a sickle cell patient receiving inadequate care. This shouldn’t be an either/or proposition. Let’s continue to support ground-breaking research while we expand education and training for medical professionals in evidenced based treatment. I look forward to the day when sickle cell patients receive the kind of treatment they need to lead healthy, pain-free lives.”

Mourning the death of Susan Solomon

Susan L. Solomon, Photo courtesy of NYSCF

We were saddened to learn today of the death of Susan Solomon, the CEO and co-founder of the New York Stem Cell Foundation (NYSCF), a non-profit organization that supports stem cell research around the world. As CEO, Ms. Solomon raised over $400M for stem cell research, helping to catalyze the field and transform the future of medical research.

The foundation announced the news on its website, saying she died after a long battle with ovarian cancer.

CIRM’s Chair Jonathan Thomas said she will be greatly missed. “We were so terribly sorry to hear about Susan’s passing.  She was a titan in our field who did immeasurable good for patients everywhere.  We have so valued our relationship with her and NYSCF through the years.”

Like many patient advocates Ms. Solomon became active when a family member was hit by disease. In her case, it was in 1992 when her ten year old son Ben was diagnosed with type 1 diabetes. A lawyer by training and a longtime business executive she put her skills to work to identify the best way to help her son, and others with type 1 diabetes. In an interview in the Wall Street Journal she says that background really helped: “As a lawyer, you learn how to learn about a new field instantly,” and, she added, “I’m really comfortable asking dumb questions.”

After much research and many conversations with scientists she concluded that stem cells were the most promising way to help patients. In 2005 she co-founded NYSCF.

Dr. Jeanne Loring, the Director of the Center for Regenerative Medicine at the Scripps Research Institute, says Ms. Solomon’s death is a huge blow to the field: “I have worked with NYSCF for the last 5 years, on the project to study neuroinflammation in space using iPSC-derived neurons.   Susan was one in a billion, she threw all of her considerable energy into starting and sustaining the only stand-alone research institute that I know of in the US dedicated to stem cell research.”

CIRM-funded stem cell-gene therapy shows promise in ALS safety trial

Senior author of the study Clive Svendsen, PhD (center)

With funding support from the California Institute for Regenerative Medicine (CIRM), Cedars-Sinai investigators have developed an investigational therapy using support cells and a protective protein that can be delivered past the blood-brain barrier. This combined stem cell and gene therapy can potentially protect diseased motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis, a fatal neurological disorder known as ALS or Lou Gehrig’s disease. 

In the first trial of its kind, the Cedars-Sinai team showed that delivery of this combined treatment is safe in humans. The findings were reported in the peer-reviewed journal Nature Medicine

What causes ALS? 

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. About 6,000 people are diagnosed with ALS each year in the U.S., and the average survival time is two to five years.  

The disease results when the cells in the brain or spinal cord that instruct muscles to move—called motor neurons—die off. People with the disease lose the ability to move their muscles and, over time, the muscles atrophy and people become paralyzed and eventually die. There is no effective therapy for the disease. 

Using Stem Cells to Treat ALS 

In a news release, senior author Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, says using stem cells shows lots of promise in treating patients with ALS.  

“We were able to show that the engineered stem cell product can be safely transplanted in the human spinal cord. And after a one-time treatment, these cells can survive and produce an important protein for over three years that is known to protect motor neurons that die in ALS,” Svendsen says.  

Aimed at preserving leg function in patients with ALS, the engineered cells could pave the way to a therapeutic option for this disease that causes progressive muscle paralysis, robbing people of their ability to move, speak and breathe.   

The study used stem cells originally designed in Svendsen’s laboratory to produce a protein called glial cell line-derived neurotrophic factor (GDNF). This protein can promote the survival of motor neurons, which are the cells that pass signals from the brain or spinal cord to a muscle to enable movement.  

In patients with ALS, diseased glial cells can become less supportive of motor neurons, and these motor neurons progressively degenerate, causing paralysis.   

By transplanting the engineered protein-producing stem cells in the central nervous system, where the compromised motor neurons are located, these stem cells can turn into new supportive glial cells and release the protective protein GDNF, which together helps the motor neurons stay alive.   

Ensuring Safety in the Trial 

The primary goal of the trial was to ensure that delivering the cells releasing GDNF to the spinal cord did not have any safety issues or negative effects on leg function.   

In this trial, none of the 18 patients treated with the therapy—developed by Cedars-Sinai scientists and funded by CIRM—had serious side effects after the transplantation, according to the data. 

Because patients with ALS usually lose strength in both legs at a similar rate, investigators transplanted the stem cell-gene product into only one side of the spinal cord so that the therapeutic effect on the treated leg could be directly compared to the untreated leg.  

After the transplantation, patients were followed for a year so the team could measure the strength in the treated and untreated legs. The goal of the trial was to test for safety, which was confirmed, as there was no negative effect of the cell transplant on muscle strength in the treated leg compared to the untreated leg.    

What’s Next? 

Investigators expect to start a new study with more patients soon. They will be targeting lower in the spinal cord and enrolling patients at an earlier stage of the disease to increase the chances of seeing effects of the cells on the progression of ALS. 

“We are very grateful to all the participants in the study,” said Svendsen. “ALS is a very tough disease to treat, and this research gives us hope that we are getting closer to finding ways to slow down this disease.”   

The Cedars-Sinai team is also using the GDNF-secreting stem cells in another CIRM-funded clinical trial for ALS, transplanting the cells into a specific brain region, called the motor cortex that controls the initiation of movement in the hand. The clinical trial is also funded by CIRM. 

The California Institute for Regenerative Medicine (CIRM) remains committed to funding research and clinical trials to treat ALS. To date, CIRM has provided $93 million in funding for research to treat ALS.  

Read the original source release of the study here.