Chemistry Nobel Prize winner Carolyn Bertozzi had a hand in early stem cell research

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Carolyn Bertozzi. Image credit: Andrew Brodhead

The 2022 Nobel Prize in Chemistry has been awarded to Carolyn R. Bertozzi of Stanford University, Morten Meldal of the University of Copenhagen, and K. Barry Sharpless of Scripps Research. The three scientists are recognized for their independent development and contributions to the field known as click chemistry and bioorthogonal chemistry. 

Sharpless and Meldal are credited with laying the foundation for click chemistry, a functional form of chemistry in which molecular building blocks snap together quickly and efficiently. But it’s Bertozzi—a Stanford professor, chemist, mentor and early CIRM grantee—who is being recognized for taking click chemistry to a new dimension and utilizing it in living organisms.

A press release from The Royal Swedish Academy of Sciences describes Bertozzi’s accomplishments as follows:  

“To map important but elusive biomolecules on the surface of cells – glycans – Bertozzi developed click reactions that work inside living organisms. Her bioorthogonal reactions take place without disrupting the normal chemistry of the cell.  

These reactions are now used globally to explore cells and track biological processes. Using bioorthogonal reactions, researchers have improved the targeting of cancer pharmaceuticals, which are now being tested in clinical trials.” 

Click chemistry and bioorthogonal reactions, the press release notes, have taken chemistry into the era of functionalism and brings the greatest benefit to humankind. 

Bertozzi celebrates her Nobel Prize win. Image courtesy Kurt Hickman and Harry Gregory for Stanford.

A Hand in Early Stem Cell Research 

Bertozzi also had a hand in early stem cell research funded by the California Institute for Regenerative Medicine (CIRM), California’s stem cell agency.  

As a recipient of a SEED Grant from the agency in 2007, Bertozzi helped jump-start human embryonic stem cell (hESC) research in California. Through that funding, Bertozzi’s lab at UC Berkeley studied the roles of cell surface sugars in the transformation of hESCs into cell types useful for the treatment of human diseases.  

“This work will contribute to a better understanding of how stem cells interact with other cells in their environment and how they mature into different cell types,” Bertozzi said. 

A Prolific Mentor

Bertozzi is also recognized as a prolific mentor, having advised more than 250 undergraduates, graduate students, and postdoctoral fellows, including CIRM Bridges alumni Ian Blong, whose experience working in Bertozzi’s lab was profiled in The Stem Cellar.  

Bertozzi founded and continues to lead the Sarafan ChEM-H Chemistry-Biology Interface Predoctoral Training Program, which helps train graduate students to bridge the gap between chemistry, biology, and medical research.  

She also helped launched a program to prepare recent college graduates from diverse and historically underrepresented backgrounds to apply for doctorate programs in the sciences. In 2022, Bertozzi was recognized with a Lifetime Mentor Award from the American Association for the Advancement of Science for her commitment to mentorship and increasing diversity in science.

CIRM congratulates Bertozzi, Meldal and Sharpless on their Nobel Prize award and for their impressive accomplishments. Read an in-depth profile of Bertozzi and her work on the Stanford Magazine website. Read more about all three scientists and their work here. Read the news release from Stanford here.

Strength forged from adversity

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Regina Karchner – Photo courtesy Nancy Ramos Photography

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 Regina Karchner. 

Regina Karchner says she feels as if she’s been a patient advocate for people with brain cancer almost from birth. When she was three, her father died of a brain tumor. When she was 16 Regina was diagnosed with brain cancer. While she was in the hospital she heard about the Children’s Brain Tumor Foundation (CBTF) and as soon as she was able she became a volunteer with the organization. Today she is a social work regional coordinator at CBTF.  

She says that as an advocate she feels she has a responsibility to help families deal with devastating news, to talk about death, and how to cope with the emotional trauma of it. She also advocates on behalf of survivors, like herself.  

“I am just such an advocate for the need for long term programming for brain cancer survivors, because it’s so different from other cancers. The emotional, cognitive and physical impacts of brain tumors are dramatic, that’s even if the individuals survive.  

“We are working with people in their 40’s who were the first group of childhood survivors and there’s nowhere to go that matches their needs, they can’t function enough to live independently and work full time. It’s a big problem in the medical world and even in schools, they don’t understand brain tumors, they don’t see it as a traumatic brain injury which it is and even the most well-intended schools don’t really know what to do or handle the patients.” 

“We found that survivors with better social skills have a better quality of life, so we are now trying to focus on kids in elementary school, giving them the social skills they need to survive and that are hard to catch up on later in life. They can get math or history or other subjects anytime, but the social skills are essential” 

Regina also serves on a CIRM Clinical Advisory Panel or CAP for a clinical trial for children with brain cancer. She says having the patient advocate at the table is vital to the success of the trial. “I help the researchers understand the needs of the patient, even understand why families don’t enroll in trials. 80% of families who have kids with brain tumors are on Medicaid so it’s a select group of people who can afford to be in these trials. Letting the researchers know that and coming up with ways to help them is so important.” 

She says it’s challenging work, but also very rewarding. “It feels wonderful to help families in a time of need. I feel I grow as a person and as a parent, I have learnt so much that helps me in my personal life and being grateful for having a healthy family and being a healthy survivor myself.”  

Judy Chou, Ph.D., Appointed to Governing Board of California’s Stem Cell & Gene Therapy Agency

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Judy Chou, Ph.D.

Judy Chou, Ph.D. has been appointed to the Independent Citizens’ Oversight Committee (ICOC), the governing Board of the California Institute for Regenerative Medicine (CIRM).

Dr. Chou is the President, CEO and a member of the Board of Directors of AltruBio, Inc. a clinical stage biotech company that is focused on developing novel antibody therapeutics for the treatment of immune inflammatory diseases.

“I am excited to join the ICOC leveraging my experience both as a scientist in the the biopharmaceutical industry and as a corporate executive to support the research and funding of life changing medicines for patients in need,” said Dr. Chou.

Dr. Chou has more than 20 years experience in drug development and biomanufacturing. Before joining AltruBio she headed the global Biotech organization at Bayer Pharmaceuticals. At Bayer she oversaw the development, manufacturing and distribution of the company’s more than $3 billion product portfolio. She also oversaw more than 2,000 employees and led the drug development and launch activities for the biologics pipeline. In addition, she also served as the site head for Bayer’s facility in Berkeley, California, the company’s largest manufacturing site in the U.S.

“We are honored and delighted to have Dr. Chou take a seat on the Board,” says Jonathan Thomas, Ph.D., J.D., Chair of the CIRM Board. “She has a remarkable career in academia, industry and in promoting diversity, equity and inclusion and will be an invaluable addition to the ICOC. We are very much looking forward to working with her.”

Dr. Chou also has had leadership roles at Pfizer, Medivation Inc., Genentech and Wyeth Biopharma. She has won several awards and in 2018 was the recipient of the Most Influential Women in Business award by the San Francisco Business Times. She is currently an advisor at the UC Berkeley Engineering School and is working to promote diversity and inclusion through her advisory board position at Silicon Valley Women in Engineering.

Dr. Chou obtained her Ph.D., at Yale, her post-doctoral training at the Max-Planck Institute in Germany and was a research faculty member at Harvard University Medical School focusing on cell biology and neuroscience.

Dr. Chou was appointed to the CIRM Board by State Treasurer Fiona Ma, as the Executive Officer of a Commercial Life Science entity. She replaces Dave Martin.

State Stem Cell & Gene Therapy Agency Sets up Support Program to Help Patients Participate in Clinical Trials

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For many patients battling deadly diseases, getting access to a clinical trial can be life-saving, but it can also be very challenging. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved a concept plan to make it financially and logistically easier for patients to take part in CIRM-funded clinical trials.

The plan will create a Patient Support Program (PSP) to provide support to California patients being evaluated or enrolled in CIRM-supported clinical trials, with a particular emphasis on helping underserved populations.

“Helping scientists develop stem cell and gene therapies is just part of what we do at CIRM. If those clinical trials and resulting therapies are not accessible to the people of California, who are making all this possible, then we have not fulfilled our mission.” says Maria T. Millan, M.D., President and CEO of CIRM.

The Patient Support Plan will offer a range of services including:

  • Clinical trial navigation, directing patients to appropriate CIRM-supported clinical trials.
  • Logistical support for patients being evaluated or enrolled in clinical trials.
  • Financial support for under resourced and underserved populations in CIRM-supported clinical trials, including the CIRM Patient Assistance Fund (PAF).  This support includes transportation/travel expenses, such as gasoline, tolls, parking, airfare, taxi, train, lodging, and meals during travel.
  • Providing nurse navigator support for the psychosocial, emotional, and practical needs of patients and their families.

The funds for the PSP are set aside under Proposition 14, the voter-approved initiative that re-funded CIRM in 2020. Under Prop 14 CIRM money that CIRM grantees earn from licensing, inventions or technologies is to be spent “offsetting the costs of providing treatments and cures arising from institute-funded research to California patients who have insufficient means to purchase such treatment or cure, including the reimbursement of patient-qualified costs for research participants.”

Currently, the CIRM Licensing Revenues and Royalties Fund has a balance of $15.6 million derived from royalty payments.

“The patient support program and financial resources will not only help patients in need, it will also help increase the likelihood that these clinical trials will succeed,” says Sean Turbeville, Ph.D., Vice President of Medical Affairs and Policy at CIRM. “We know cell and gene therapies can be particularly challenging for patients and their families. The financial challenges, the long-distance traveling, extended evaluation, and family commitments can make it difficult to enroll and retain patients. The aim of the PSP is to change that.”

The overall objective of this funding opportunity is to establish a statewide program that, over five years, is expected to support hundreds of patients in need as they participate in the growing number of CIRM-supported clinical trials. The program is expected to cost between $300,000 to $500,000 a year. That money will come from the Medical Affairs budget and not out of the patient assistance fund.

The first phase of the program will identify an organization, through a competitive process, that has the expertise to provide patient support services including:

  • Maintaining a call and support center.
  • Assessing patient eligibility for financial assistance.
  • Reporting to CIRM on patients needs and center performance

 You can find more information about the Patient Support Program on our website here and here.

How the Tooth Fairy is helping unlock the secrets of autism

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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

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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)!

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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

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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

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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

/ Kevin McCormack / 3 Comments

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 Tobi.

Michelle, Jeff and baby Tobi

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

And Michelle says Tobi 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.”