Progress in the fight against Sickle Cell Disease

Marissa Cors, sickle cell disease patient advocate

Last November Marissa Cors, a patient advocate in the fight against Sickle Cell Disease (SCD), told the Stem Cellar “A stem cell cure will end generations of guilt, suffering, pain and early death. It will give SCD families relief from the financial, emotional and spiritual burden of caring someone living with SCD. It will give all of us an opportunity to have a normal life. Go to school, go to work, live with confidence.” With each passing month it seems we are getting closer to that day.

CIRM is funding four clinical trials targeting SCD and another project we are supporting has just been given the green light by the Food and Drug Administration to start a clinical trial. Clearly progress is being made.

Yesterday we got a chance to see that progress. We held a Zoom event featuring Marissa Cors and other key figures in the fight against SCD, CIRM Science Officer Dr. Ingrid Caras and Evie Junior. Evie is a pioneer in this struggle, having lived with sickle cell all his life but now hoping to live his life free of the disease. He is five months past a treatment that holds out the hope of eradicating the distorted blood cells that cause such devastation to people with the disease.

You can listen to his story, and hear about the other progress being made. Here’s a recording of the Zoom event.

You can also join Marissa every week on her live event on Facebook, Sickle Cell Experience Live.

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.

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.

Graphite Bio launches and will prepare for clinical trial based on CIRM-funded research

Josh Lehrer, M.D., CEO of Graphite Bio

This week saw the launch of the 45th startup company enabled by CIRM funding of translational research at California academic institutions. Graphite Bio officially launched with the help of $45M in funding led by bay area venture firms Versant Ventures and Samsara BioCapital to spinout a novel CRISPR gene editing platform from Stanford University to treat severe diseases. Graphite Bio’s lead candidate is for sickle cell disease and it harnesses CRISPR gene correction technology to correct the single DNA mutation in sickle cell disease and to restore normal hemoglobin expression in the red blood cells of sickle cell patients (Learn more about CRISPR from a previous blog post linked here).

Matt Porteus, M.D., Ph.D (left) and Maria Grazia Roncarolo, M.D. (right)
Graphite Bio scientific founders

Matt Porteus, M.D., Ph.D and Maria Grazia Roncarolo, M.D., both from Stanford University, are the company’s scientific founders. Dr. Porteus, Dr. Roncarolo, and the Stanford team are currently supported by a CIRM  late stage preclinical grant  to complete the final preclinical studies and to file an Investigational New Drug application with the FDA, which will enable Graphite Bio to commence clinical studies of the CRISPR sickle cell disease gene therapy candidate in sickle cell patients in 2021.

Josh Lehrer, M.D., was appointed CEO of Graphite Bio and elaborated on the company’s gene editing approach in a news release.

“Our flexible, site-specific approach is extremely powerful and could be used to definitively correct the underlying causes of many severe genetic diseases, and also is applicable to broader disease areas. With backing from Versant and Samsara, we look forward to progressing our novel medicines into the clinic for patients with high unmet needs.”

In a press release, Dr. Porteus take a retrospective look on his preclinical research and its progress towards a clinical trial.

“It is gratifying to see our work on new gene editing approaches being translated into novel therapies. I’m very excited to be working with Versant again on a start-up and I look forward to collaborating with Samsara and the Graphite Bio team to bring a new generation of genetic treatments to patients.”

CIRM’s funding of late stage preclinical projects such this one is critical to its funding model, which de-risks the discovery, translational development and clinical proof of concept of innovative stem cell-based treatments until they can attract industry partnerships. You can learn more about CIRM-enabled spinout companies and CIRM’s broader effort to facilitate industry partnering for its portfolio projects on CIRM’s Industry Alliance Program website.

You can contact CIRM’s Director of Business Development at the email below to learn more about the Industry Alliance Program.

Shyam Patel, Ph.D.
Director, Business Development
Email: spatel@cirm.ca.gov

Building a progressive pipeline

Dr. Kelly Shepard

By Dr. Kelly Shepard

One of our favorite things to do at CIRM is deliver exciting news about CIRM projects. This usually entails discussion of recent discoveries that made headlines, or announcing the launch of a new CIRM-funded clinical trial …. tangible signs of progress towards addressing unmet medical needs through advances in stem technology.

But there are equally exciting signs of progress that are not always so obvious to the untrained eye-  those that we are privileged to witness behind the scenes at CIRM. These efforts don’t always lead to a splashy news article or even to a scientific publication, but they nonetheless drive the evolution of new ideas and can help steer the field away from futile lines of investigation. Dozens of such projects are navigating uncharted waters by filling knowledge gaps, breaking down technical barriers, and working closely with regulatory agencies to define novel and safe paths to the clinic.

These efforts can remain “hidden” because they are in the intermediate stages of the long, arduous and expensive journey from “bench to beside”.  For the pioneering projects that CIRM funds, this journey is unique and untrod, and can be fraught with false starts. But CIRM has developed tools to track the momentum of these programs and provide continuous support for those with the most promise. In so doing, we have watched projects evolve as they wend their way to the clinic. We wanted to share a few examples of how we do this with our readers, but first… a little background for our friends who are unfamiliar with the nuts and bolts of inventing new medicines.

A common metaphor for bringing scientific discoveries to market is a pipeline, which begins in a laboratory where a discovery occurs, and ends with government approval to commercialize a new medicine, after it is proven to be safe and effective. In between discovery and approval is a stage called “Translation”, where investigators develop ways to transition their “research level” processes to “clinically compatible” ones, which only utilize substances that are of certified quality for human use. 

Investigators must also work out novel ways to manufacture the product at larger scale and transition the methods used for testing in animal models to those that can be implemented in human subjects.

A key milestone in Translation is the “preIND” (pre Investigational New Drug (IND) meeting, where an investigator presents data and plans to the US Food and Drug Administration (FDA) for feedback before next stage of development begins, the pivotal testing needed to show it is both safe and effective.

These “IND enabling studies” are rigorous but necessary to support an application for an IND and the initiation of clinical trials, beginning with phase 1 to assess safety in a small number of individuals, and phase 2, where an expanded group is evaluated to see if the therapy has any benefits for the patient. Phase 3 trials are studies of very large numbers of individuals to gain definitive evidence of safety and therapeutic effect, generally the last step before applying to the FDA for market approval. An image of the pipeline and the stages described are provided in our diagram below.

The pipeline can be notoriously long and tricky, with plenty of twists, turns, and unexpected obstacles along the way. Many more projects enter than emerge from this gauntlet, but as we see from these examples of ‘works in progress”, there is a lot of momentum building.

Caption for Graphic: This graphic shows the number of CIRM-funded projects and the stages they have progressed through multiple rounds of CIRM funding. For example, the topmost arrow shows that are about 19 projects at the translational stage of the pipeline that received earlier support through one of CIRM’s Discovery stage programs. Many of these efforts came out of our pre-2016 funding initiatives such as Early Translation, Basic Biology and New Faculty Awards. In another example, you can see that about 15 awards that were first funded by CIRM at the IND enabling stage have since progressed into a phase 1 or phase 2 clinical trials. While most of these efforts also originated in some of CIRM’s pre-2016 initiatives such as the Disease Team Awards, others have already progressed from CIRM’s newer programs that were launched as part of the “2.0” overhaul in 2016 (CLIN1).

The number of CIRM projects that have evolved and made their way down the pipeline with CIRM support is impressive, but it is clearly an under-representation, as there are other projects that have progressed outside of CIRM’s purview, which can make things trickier to verify.

We also track projects that have spun off or been licensed to commercial organizations, another very exciting form of “progression”. Perhaps those will contribute to another blog for another day! In the meantime, here are a just a few examples of some of the progressors that are depicted on the graphic.

Project: stem cell therapy to enhance bone healing in the elderly

– Currently funded stage: IND enabling development, CLIN1-11256 (Dr. Zhu, Ankasa Regenerative Therapeutics)

– Preceded by preIND-enabling studies, TRAN1-09270 (Dr. Zhu, Ankasa Regenerative Therapeutics)

– Preceded by discovery stage research grant TR1-01249 (Dr. Longaker and Dr. Helm, Stanford)

Project: embryonic stem cell derived neural cell therapy for Huntington Disease

– Currently funded stage: IND enabling development, CLIN1-10953 (Dr. Thompson, UC Irvine)

– Preceded by preIND-enabling studies, PC1-08117 (Dr. Thompson, UC Irvine)

– Preceded by discovery stage research grant (TR2-01841) (Dr. Thompson, UC Irvine)

Project: gene-modified hematopoietic stem cells for Artemis Deficient severe combined immunodeficiency (SCID)

– Currently funded stage: Phase 1 clinical trial CLIN2-10830 (Dr. Cowan, UC San Francisco)

– Preceded by IND enabling development, CLIN1-08363 (Dr. Puck, UC San Francisco)

– Preceded by discovery stage research grant, TR3-05535  (Dr. Cowan, UC San Francisco)

Project: retinal progenitor cell therapy for retinitis pigmentosa

– Currently funded stage: Phase 2 and 2b clinical trials, CLIN2-11472, CLIN2-09698 (Dr. Klassen, JCyte, Inc.)

– Preceded by IND enabling development, DR2A-05739 (Dr. Klassen, UC Irvine)

– Preceded by discovery stage research grant, TR2-01794 (Dr. Klassen, UC Irvine)

Meet the people who are changing the future

Kristin MacDonald

Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.

I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.

Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.

That’s when you know the treatment works. At least for Rosie.

There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.

It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.

Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.

And it’s free!

You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.

We hope to see you there.

Two studies identify a molecule that could be used to block Zika virus and kill cancer cells

Dr. Tariq Rana (left) and Dr. Jeremy Rich (right) both lead independent teams at UC San Diego that identified a molecule, αvβ5 integrin, as the Zika virus’ key to getting into brain stem cells

Zika virus is caused by a virus transmitted by Aedes mosquitoes. People usually develop mild symptoms that include fever, rash, and muscle and joint pain. However, Zika virus infection during pregnancy can lead to much more serious problems. The virus causes infants to be born with microcephaly, a condition in which the brain does not develop properly, resulting in an abnormally small head. In 2015-2016, the rapid spread of the virus was observed in Latin America and the Caribbean, increasing the urgency of understanding how the virus affected brain development.

Working independently, Dr. Tariq Rana and Dr. Jeremy Rich from UC San Diego identified the same molecule, αvβ5 integrin, as the Zika virus’ key to entering brain stem cells. The two studies, with the aid of CIRM funding, discovered how to take advantage of the molecule in order to block the Zika virus from infecting cells. In addition to this, they were able to turn it into something useful: a way to destroy brain cancer stem cells.

In the first study, Dr. Rana and his team used CRISPR gene editing on brain cancer stem cells to delete individual genes, which was done to see which genes are required for the Zika virus to enter the cells. They discovered that the gene responsible for αvβ5 integrin also enabled the Zika virus.

In a press release by UC San Diego, Dr. Rana elaborates on the importance of his findings.

“…we found Zika uses αvβ5, which is unique. When we further examined αvβ5 expression in brain, it made perfect sense because αvβ5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that αvβ5 is the key contributor to Zika’s ability to infect brain cells.”

In the second study, Dr. Rich and his team use an antibody to block αvβ5 integrin and found that it prevented the virus from infecting brain cancer stem cells and normal brain stem cells. The team then went on to block αvβ5 integrin in a mouse model for glioblastoma, an aggressive type of brain tumor, by using an antibody or deactivating the gene responsible for the molecule. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. 

Dr. Rich then partnered with Dr. Alysson Muotri at UC San Diego to transplant glioblastoma tumors into laboratory “mini-brains” that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the mini-brains. Additionally, blocking αvβ5 integrin reversed that anti-cancer activity, further demonstrating the molecule’s crucial role in Zika virus’ ability to destroy cells.

In the same UC San Diego press release, Dr. Rich talks about how understanding Zika virus could help in treating glioblastoma.

“While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma.”

Dr. Rana’s full study was published in Cell Reports and Dr. Rich’s full study was published in Cell Stem Cell.

Facebook Live: Ask the Stem Cell Team

On December 12th we hosted our latest ‘Facebook Live: Ask the Stem Cell Team’ event. This time around we really did mean team. We had a host of our Science Officers answering questions from friends and supporters of CIRM. We got a lot of questions and didn’t have enough time to address them all. So here’s answers to all the questions.

What are the obstacles to using partial cellular reprogramming to return people’s entire bodies to a youthful state. Paul Hartman.  San Leandro, California

Dr. Kelly Shepard

Dr. Kelly Shepard: Certainly, scientists have observed that various manipulations of cells, including reprogramming, partial reprogramming, de-differentiation and trans-differentiation, can restore or change properties of cells, and in some cases, these changes can reflect a more “youthful” state, such as having longer telomeres, better proliferative capacity, etc. However, some of these same rejuvenating properties, outside of their normal context, could be harmful or deadly, for example if a cell began to grow and divide when or where it shouldn’t, similar to cancer. For this reason, I believe the biggest obstacles to making this approach a reality are twofold: 1)  our current, limited understanding of the nature of partially reprogrammed cells; and 2) our inability to control the fate of those cells that have been partially reprogrammed, especially if they are inside a living organism.  Despite the challenges, I think there will be step wise advances where these types of approaches will be applied, starting with specific tissues. For example, CIRM has recently funded an approach that uses reprogramming to make “rejuvenated” versions of T cells for fighting lung cancer.  There is also a lot of interest in using such approaches to restore the reparative capacity of aged muscle. Perhaps some successes in these more limited areas will be the basis for expanding to a broader use.

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STROKE

What’s going on with Stanford’s stem cell trials for stroke? I remember the first trial went really well In 2016 have not heard anything about since? Elvis Arnold

Dr. Lila Collins

Dr. Lila Collins: Hi Elvis, this is an evolving story.  I believe you are referring to SanBio’s phase 1/2a stroke trial, for which Stanford was a site. This trial looked at the safety and feasibility of SanBio’s donor or allogeneic stem cell product in chronic stroke patients who still had motor deficits from their strokes, even after completing physical therapy when natural recovery has stabilized.  As you note, some of the treated subjects had promising motor recoveries. 

SanBio has since completed a larger, randomized phase 2b trial in stroke, and they have released the high-level results in a press release.  While the trial did not meet its primary endpoint of improving motor deficits in chronic stroke, SanBio conducted a very similar randomized trial in patients with stable motor deficits from chronic traumatic brain injury (TBI).  In this trial, SanBio saw positive results on motor recovery with their product.  In fact, this product is planned to move towards a conditional approval in Japan and has achieved expedited regulatory status in the US, termed RMAT, in TBI which means it could be available more quickly to patients if all goes well.  SanBio plans to continue to investigate their product in stroke, so I would stay tuned as the work unfolds. 

Also, since you mentioned Stanford, I should note that Dr Gary Steinberg, who was a clinical investigator in the SanBio trial you mentioned, will soon be conducting a trial with a different product that he is developing, neural progenitor cells, in chronic stroke.  The therapy looks promising in preclinical models and we are hopeful it will perform well for patients in the clinic.

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I am a stroke survivor will stem cell treatment able to restore my motor skills? Ruperto

Dr. Lila Collins:

Hi Ruperto. Restoring motor loss after stroke is a very active area of research.  I’ll touch upon a few ongoing stem cell trials.  I’d just like to please advise that you watch my colleague’s comments on stem cell clinics (these can be found towards the end of the blog) to be sure that any clinical research in which you participate is as safe as possible and regulated by FDA.

Back to stroke, I mentioned SanBio’s ongoing work to address motor skill loss in chronic stroke earlier.  UK based Reneuron is also conducting a phase 2 trial, using a neural progenitor cell as a candidate therapy to help recover persistent motor disability after stroke (chronic).  Dr Gary Steinberg at Stanford is also planning to conduct a clinical trial of a human embryonic stem cell-derived neuronal progenitor cell in stroke.

There is also promising work being sponsored by Athersys in acute stroke. Athersys published results from their randomized, double blinded placebo controlled Ph2 trial of their Multistem product in patients who had suffered a stroke within 24-48 hours.  After intravenous delivery, the cells improved a composite measure of stroke recovery, including motor recovery.  Rather than acting directly on the brain, Multistem seems to work by traveling to the spleen and reducing the inflammatory response to a stroke that can make the injury worse.

Athersys is currently recruiting a phase 3 trial of its Multistem product in acute stroke (within 1.5 days of the stroke).  The trial has an accelerated FDA designation, called RMAT and a special protocol assessment.  This means that if the trial is conducted as planned and it reaches the results agreed to with the FDA, the therapy could be cleared for marketing.  Results from this trial should be available in about two years. 

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Questions from several hemorrhagic stroke survivors who say most clinical trials are for people with ischemic strokes. Could stem cells help hemorrhagic stroke patients as well?

Dr. Lila Collins:

Regarding hemorrhagic stroke, you are correct the bulk of cell therapies for stroke target ischemic stroke, perhaps because this accounts for the vast bulk of strokes, about 85%.

That said, hemorrhagic strokes are not rare and tend to be more deadly.  These strokes are caused by bleeding into or around the brain which damages neurons.  They can even increase pressure in the skull causing further damage.  Because of this the immediate steps treating these strokes are aimed at addressing the initial bleeding insult and the blood in the brain.

While most therapies in development target ischemic stroke, successful therapies developed to repair neuronal damage or even some day replace lost neurons, could be beneficial after hemorrhagic stroke as well.

We are aware of a clinical trial targeting acute hemorrhagic stroke that is being run by the Mayo clinic in Jacksonville Florida.

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I had an Ischemic stroke in 2014, and my vision was also affected. Can stem cells possibly help with my vision issues. James Russell

Dr. Lila Collins:

Hi James. Vision loss from stroke is complex and the type of loss depends upon where the stroke occurred (in the actual eye, the optic nerve or to the other parts of the brain controlling they eye or interpreting vision).  The results could be:

  1. Visual loss from damage to the retina
  2. You could have a normal eye with damage to the area of the brain that controls the eye’s movement
  3. You could have damage to the part of the brain that interprets vision.

You can see that to address these various issues, we’d need different cell replacement approaches to repair the retina or the parts of the brain that were damaged. 

Replacing lost neurons is an active effort that at the moment is still in the research stages.  As you can imagine, this is complex because the neurons have to make just the right connections to be useful. 

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VISION

Is there any stem cell therapy for optical nerve damage? Deanna Rice

Dr. Ingrid Caras

Dr. Ingrid Caras: There is currently no proven stem cell therapy to treat optical nerve damage, even though there are shady stem cell clinics offering treatments.  However, there are some encouraging early gene therapy studies in mice using a virus called AAV to deliver growth factors that trigger regeneration of the damaged nerve. These studies suggest that it may be possible to restore at least some visual function in people blinded by optic nerve damage from glaucoma

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I read an article about ReNeuron’s retinitis pigmentosa clinical trial update.  In the article, it states: “The company’s treatment is a subretinal injection of human retinal progenitors — cells which have almost fully developed into photoreceptors, the light-sensing retinal cells that make vision possible.” My question is: If they can inject hRPC, why not fully developed photoreceptors? Leonard

Dr. Kelly Shepard: There is evidence from other studies, including from other tissue types such as blood, pancreas, heart and liver, that fully developed (mature) cell types tend not to engraft as well upon transplantation, that is the cells do not establish themselves and survive long term in their new environment. In contrast, it has been observed that cells in a slightly less “mature” state, such as those in the progenitor stage, are much more likely to establish themselves in a tissue, and then differentiate into more mature cell types over time. This question gets at the crux of a key issue for many new therapies, i.e. what is the best cell type to use, and the best timing to use it.

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My question for the “Ask the Stem Cell Team” event is: When will jCyte publish their Phase IIb clinical trial results. Chris Allen

Dr. Ingrid Caras: The results will be available sometime in 2020.

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I understand the hRPC cells are primarily neurotropic (rescue/halt cell death); however, the literature also says hRPC can become new photoreceptors.  My questions are: Approximately what percentage develop into functioning photoreceptors? And what percentage of the injected hRPC are currently surviving? Leonard Furber, an RP Patient

Dr. Kelly Shepard: While we can address these questions in the lab and in animal models, until there is a clinical trial, it is not possible to truly recreate the environment and stresses that the cells will undergo once they are transplanted into a human, into the site where they are expected to survive and function. Thus, the true answer to this question may not be known until after clinical trials are performed and the results can be evaluated. Even then, it is not always possible to monitor the fate of cells after transplantation without removing tissues to analyze (which may not be feasible), or without being able to transplant labeled cells that can be readily traced.

Dr. Ingrid Caras – Although the cells have been shown to be capable of developing into photoreceptors, we don’t know if this actually happens when the cells are injected into a patient’s eye.   The data so far suggest that the cells work predominantly by secreting growth factors that rescue damaged retinal cells or even reverse the damage. So one possible outcome is that the cells slow or prevent further deterioration of vision. But an additional possibility is that damaged retinal cells that are still alive but are not functioning properly may become healthy and functional again which could result in an improvement in vision.

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DIABETES

What advances have been made using stem cells for the treatment of Type 2 Diabetes? Mary Rizzo

Dr. Ross Okamura

Dr. Ross Okamura: Type 2 Diabetes (T2D) is a disease where the body is unable to maintain normal glucose levels due to either resistance to insulin-regulated control of blood sugar or insufficient insulin production from pancreatic beta cells.  The onset of disease has been associated with lifestyle influenced factors including body mass, stress, sleep apnea and physical activity, but it also appears to have a genetic component based upon its higher prevalence in certain populations. 

Type 1 Diabetes (T1D) differs from T2D in that in T1D patients the pancreatic beta cells have been destroyed by the body’s immune system and the requirement for insulin therapy is absolute upon disease onset rather than gradually developing over time as in many T2D cases.  Currently the only curative approach to alleviate the heavy burden of disease management in T1D has been donor pancreas or islet transplantation. However, the supply of donor tissue is small relative to the number of diabetic patients.  Donor islet and pancreas transplants also require immune suppressive drugs to prevent allogenic immune rejection and the use of these drugs carry additional health concerns.  However, for some patients with T1D, especially those who may develop potentially fatal hypoglycemia, immune suppression is worth the risk.

To address the issue of supply, there has been significant activity in stem cell research to produce insulin secreting beta cells from pluripotent stem cells and recent clinical data from Viacyte’s CIRM funded trial indicates that implanted allogeneic human stem cell derived cells in T1D patients can produce circulating c-peptide, a biomarker for insulin.  While the trial is not designed specifically to cure insulin-dependent T2D patients, the ability to produce and successfully engraft stem cell-derived beta cells would be able to help all insulin-dependent diabetic patients.

It’s also worth noting that there is a sound scientific reason to clinically test a patient-derived pluripotent stem cell-based insulin-producing cells in insulin-dependent T2D diabetic patients; the cells in this case could be evaluated for their ability to cure diabetes in the absence of needing to prevent both allogeneic and autoimmune responses.

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SPINAL CORD INJURY

Is there any news on clinical trials for spinal cord injury? Le Ly

Kevin McCormack: The clinical trial CIRM was funding, with Asterias (now part of a bigger company called Lineage Cell Therapeutics, is now completed and the results were quite encouraging. In a news release from November of 2019 Brian Culley, CEO of Lineage Cell Therapeutics, described the results this way.

“We remain extremely excited about the potential for OPC1 (the name of the therapy used) to provide enhanced motor recovery to patients with spinal cord injuries. We are not aware of any other investigative therapy for SCI (spinal cord injury) which has reported as encouraging clinical outcomes as OPC1, particularly with continued improvement beyond 1 year. Overall gains in motor function for the population assessed to date have continued, with Year 2 assessments measuring the same or higher than at Year 1. For example, 5 out of 6 Cohort 2 patients have recovered two or more motor levels on at least one side as of their Year 2 visit whereas 4 of 6 patients in this group had recovered two motor levels as of their Year 1 visit. To put these improvements into perspective, a one motor level gain means the ability to move one’s arm, which contributes to the ability to feed and clothe oneself or lift and transfer oneself from a wheelchair. These are tremendously meaningful improvements to quality of life and independence. Just as importantly, the overall safety of OPC1 has remained excellent and has been maintained 2 years following administration, as measured by MRI’s in patients who have had their Year 2 follow-up visits to date. We look forward to providing further updates on clinical data from SCiStar as patients continue to come in for their scheduled follow up visits.”

Lineage Cell Therapeutics plans to meet with the FDA in 2020 to discuss possible next steps for this therapy.

In the meantime the only other clinical trial I know that is still recruiting is one run by a company called Neuralstem. Here is a link to information about that trial on the www.clinicaltrials.gov website.

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ALS

Now that the Brainstorm ALS trial is finished looking for new patients do you have any idea how it’s going and when can we expect to see results? Angela Harrison Johnson

Dr. Ingrid Caras: The treated patients have to be followed for a period of time to assess how the therapy is working and then the data will need to be analyzed.  So we will not expect to see the results probably for another year or two.

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AUTISM

Are there treatments for autism or fragile x using stem cells? Magda Sedarous

Dr. Kelly Shepard: Autism and disorders on the autism spectrum represent a collection of many different disorders that share some common features, yet have different causes and manifestations, much of which we still do not understand. Knowing the origin of a disorder and how it affects cells and systems is the first step to developing new therapies. CIRM held a workshop on Autism in 2009 to brainstorm potential ways that stem cell research could have an impact. A major recommendation was to exploit stem cells and new technological advances to create cells and tissues, such as neurons, in the lab from autistic individuals that could then be studied in great detail.  CIRM followed this recommendation and funded several early-stage awards to investigate the basis of autism, including Rett Syndrome, Fragile X, Timothy Syndrome, and other spectrum disorders. While these newer investigations have not yet led to therapies that can be tested in humans, this remains an active area of investigation. Outside of CIRM funding, we are aware of more mature studies exploring the effects of umbilical cord blood or other specific stem cell types in treating autism, such as an ongoing clinical trial conducted at Duke University.

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PARKINSON’S DISEASE

What is happening with Parkinson’s research? Hanifa Gaphoor

Dr. Kent Fitzgerald

Dr. Kent Fitzgerald: Parkinson’s disease certainly has a significant amount of ongoing work in the regenerative medicine and stem cell research. 

The nature of cell loss in the brain, specifically the dopaminergic cells responsible for regulating the movement, has long been considered a good candidate for cell replacement therapy.  

This is largely due to the hypothesis that restoring function to these cells would reverse Parkinson’s symptoms. This makes a lot of sense as front line therapy for the disease for many years has been dopamine replacement through L-dopa pills etc.  Unfortunately, over time replacing dopamine through a pill loses its benefit, whereas replacing or fixing the cells themselves should be a more permanent fix. 

Because a specific population of cells in one part of the brain are lost in the disease, multiple labs and clinicians have sought to replace or augment these cells by transplantation of “new” functional cells able to restore function to the area an theoretically restore voluntary motor control to patients with Parkinson’s disease. 

Early clinical research showed some promise, however also yielded mixed results, using fetal tissue transplanted into the brains of Parkinson’s patients.   As it turns out, the cell types required to restore movement and avoid side effects are somewhat nuanced.  The field has moved away from fetal tissue and is currently pursuing the use of multiple stem cell types that are driven to what is believed to be the correct subtype of cell to repopulate the lost cells in the patient. 

One project CIRM sponsored in this area with Jeanne Loring sought to develop a cell replacement therapy using stem cells from the patients themselves that have been reprogrammed into the kinds of cell damaged by Parkinson’s.  This type of approach may ultimately avoid issues with the cells avoiding rejection by the immune system as can be seen with other types of transplants (i.e. liver, kidney, heart etc).

Still, others are using cutting edge gene therapy technology, like the clinical phase project CIRM is sponsoring with Krystof Bankiewicz to investigate the delivery of a gene (GDNF) to the brain that may help to restore the activity of neurons in the Parkinson’s brain that are no longer working as they should. 

The bulk of the work in the field of PD at the present remains centered on replacing or restoring the dopamine producing population of cells in the brain that are affected in disease.   

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HUNTINGTON’S DISEASE

Any plans for Huntington’s? Nikhat Kuchiki

Dr. Lisa Kadyk

Dr. Lisa Kadyk: The good news is that there are now several new therapeutic approaches to Huntington’s Disease that are at various stages of preclinical and clinical development, including some that are CIRM funded.   One CIRM-funded program led by Dr. Leslie Thompson at UC Irvine is developing a cell-based therapeutic that consists of neural stem cells that have been manufactured from embryonic stem cells.   When these cells are injected into the brain of a mouse that has a Huntington’s Disease mutation, the cells engraft and begin to differentiate into new neurons.  Improvements are seen in the behavioral and electrophysiological deficits in these mutant mice, suggesting that similar improvements might be seen in people with the disease.   Currently, CIRM is funding Dr. Thompson and her team to carry out rigorous safety studies in animals using these cells, in preparation for submitting an application to the FDA to test the therapy in human patients in a clinical trial.   

There are other, non-cell-based therapies also being tested in clinical trials now, using  anti-sense oligonucleotides (Ionis, Takeda) to lower the expression of the Huntington protein.  Another HTT-lowering approach is similar – but uses miRNAs to lower HTT levels (UniQure, Voyager)

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TRAUMATIC BRAIN INJURY (TBI)

My 2.5 year old son recently suffered a hypoxic brain injury resulting in motor and speech disabilities. There are several clinical trials underway for TBI in adults. My questions are:

  • Will the results be scalable to pediatric use and how long do you think it would take before it is available to children?
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  • I’m wondering why the current trials have chosen to go the route of intracranial injections as opposed to something slightly less invasive like an intrathecal injection?
  • Is there a time window period in which stem cells should be administered by, after which the administration is deemed not effective?

Dr. Kelly Shepard:  TBI and other injuries of the nervous system are characterized by a lot of inflammation at the time of injury, which is thought to interfere with the healing process- and thus some approaches are intended to be delivered after that inflammation subsides. However, we are aware of approaches that intend to deliver a therapy to a chronic injury, or one that has occurred  previously. Thus, the answer to this question may depend on how the intended therapy is supposed to work. For example, is the idea to grow new neurons, or is it to promote the survival of neurons of other cells that were spared by the injury? Is the therapy intended to address a specific symptom, such as seizures? Is the therapy intended to “fill a gap” left behind after inflammation subsides, which might not restore all function but might ameliorate certain symptoms.? There is still a lot we don’t understand about the brain and the highly sophisticated network of connections that cannot be reversed by only replacing neurons, or only reducing inflammation, etc. However, if trials are well designed, they should yield useful information even if the therapy is not as effective as hoped, and this information will pave the way to newer approaches and our technology and understanding evolves.

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We have had a doctor recommending administering just the growth factors derived from MSC stem cells. Does the science work that way? Is it possible to isolate the growth factors and boost the endogenous growth factors by injecting allogenic growth factors?

Dr. Stephen Lin

Dr. Stephen Lin:  Several groups have published studies on the therapeutic effects in non-human animal models of using nutrient media from MSC cultures that contain secreted factors, or extracellular vesicles from cells called exosomes that carry protein or nucleic acid factors.  Scientifically it is possible to isolate the factors that are responsible for the therapeutic effect, although to date no specific factor or combination of factors have been identified to mimic the effects of the undefined mixtures in the media and exosomes.  At present no regulatory approved clinical therapy has been developed using this approach. 

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PREDATORY STEM CELL CLINICS

What practical measures are being taken to address unethical practitioners whose bad surgeries are giving stem cell advances a bad reputation and are making forward research difficult? Kathy Jean Schultz

Dr. Geoff Lomax

Dr. Geoff Lomax: Terrific question! I have been doing quite a bit research into the history of this issue of unethical practitioners and I found an 1842 reference to “quack medicines.” Clearly this is nothing new. In that day, the author appealed to make society “acquainted with the facts.”

In California, we have taken steps to (1) acquaint patients with the facts about stem cell treatments and (2) advance FDA authorized treatments for unmet medical needs.

  • First, CIRM work with Senator Hernandez in 2017 to write a law the requires provides to disclose to patient that a stem cell therapy has not been approved by the Food and Drug administration.
  • We continue to work with the State Legislature and Medical Board of California to build on policies that require accurate disclosure of the facts to patients.
  • Second, our clinical trial network the — Alpha Stem Cell Clinics – have supported over 100 FDA-authorized clinical trials to advance responsible clinical research for unmet medical needs.

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I’m curious if adipose stem cell being used at clinics at various places in the country is helpful or beneficial? Cheri Hicks

Adipose tissue has been widely used particularly in plastic and reconstructive surgery. Many practitioners suggest adipose cells are beneficial in this context. With regard to regenerative medicine and / or the ability to treat disease and injury, I am not aware of any large randomized clinical trials that demonstrate the safety and efficacy of adipose-derived stem cells used in accordance with FDA guidelines.

I went to a “Luncheon about Stem Cell Injections”. It sounded promising. I went thru with it and got the injections because I was desperate from my knee pain. The price of stem cell injections was $3500 per knee injection. All went well. I have had no complications, but haven’t noticed any real major improvement, and here I am a year later. My questions are:

 1) I wonder on where the typical injection cells are coming from?

  2) I wonder what is the actual cost of the cells?

3) What kind of results are people getting from all these “pop up” clinics or established clinics that are adding this to there list of offerings?

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Dr. Geoff Lomax: You raise a number of questions and point here; they are all very good and it’s is hard to give a comprehensive response to each one, but here is my reaction:

  • There are many practitioners in the field of orthopedics who sincerely believe in the potential of cell-based treatments to treat injury / pain
  • Most of the evidence presented is case reports that individuals have benefited
  • The challenge we face is not know the exact type of injury and cell treatments used.
  • Well controlled clinical trials would really help us understand for what cells (or cell products) and for what injury would be helpful
  • Prices of $3000 to $5000 are not uncommon, and like other forms of private medicine there is often a considerable mark-up in relation to cost of goods.
  • You are correct that there have not been reports of serious injury for knee injections
  • However the effectiveness is not clear while simultaneously millions of people have been aided by knee replacements.

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Do stem cells have benefits for patients going through chemotherapy and radiation therapy? Ruperto

Dr. Kelly Shepard: The idea that a stem cell therapy could help address effects of chemotherapy or radiation is being and has been pursued by several investigators over the years, including some with CIRM support. Towards the earlier stages, people are looking at the ability of different stem cell-derived neural cell preparations to replace or restore function of certain brain cells that are damaged by the effects of chemotherapy or radiation. In a completely different type of approach, a group at City of Hope is exploring whether a bone marrow transplant with specially modified stem cells can provide a protective effect against the chemotherapy that is used to treat a form of brain cancer, glioblastoma. This study is in the final stage of development that, if all goes well, culminates with application to the FDA to allow initiation of a clinical trial to test in people.

Dr. Ingrid Caras: That’s an interesting and valid question.  There is a Phase 1 trial ongoing that is evaluating a novel type of stem/progenitor cell from the umbilical cord of healthy deliveries.  In animal studies, these cells have been shown to reduce the toxic effects of chemotherapy and radiation and to speed up recovery. These cells are now being tested in a First-in-human clinical trial in patients who are undergoing high-dose chemotherapy to treat their disease.

There is a researcher at Stanford, Michelle Monje, who is investigating that the role of damage to stem cells in the cognitive problems that sometimes arise after chemo- and radiation therapy (“chemobrain”).  It appears that damage to stem cells in the brain, especially those responsible for producing oligodendrocytes, contributes to chemobrain.  In CIRM-funded work, Dr. Monje has identified small molecules that may help prevent or ameliorate the symptoms of chemobrain.

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Is it possible to use a technique developed to fight one disease to also fight another? For instance, the bubble baby disease, which has cured (I think) more than 50 children, may also help fight sickle cell anemia?  Don Reed.

Dr. Lisa Kadyk: Hi Don. Yes, the same general technique can often be applied to more than one disease, although it needs to be “customized” for each disease.   In the example you cite, the technique is an “autologous gene-modified bone marrow transplant” – meaning the cells come from the patient themselves.  This technique is relevant for single gene mutations that cause diseases of the blood (hematopoietic) system.  For example, in the case of “bubble baby” diseases, a single mutation can cause failure of immune cell development, leaving the child unable to fight infections, hence the need to have them live in a sterile “bubble”.   To cure that disease, blood stem cells, which normally reside in the bone marrow, are collected from the patient and then a normal version of the defective gene is introduced into the cells, where it is incorporated into the chromosomes.   Then, the corrected stem cells are transplanted back into the patient’s body, where they can repopulate the blood system with cells expressing the normal copy of the gene, thus curing the disease.  

A similar approach could be used to treat sickle cell disease, since it is also caused by a single gene mutation in a gene (beta hemoglobin) that is expressed in blood cells.  The same technique would be used as I described for bubble baby disease but would differ in the gene that is introduced into the patient’s blood stem cells. 

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Is there any concern that CIRM’s lack of support in basic research will hamper the amount of new approaches that can reach clinical stages? Jason

Dr. Kelly Shepard: CIRM always has and continues to believe that basic research is vital to the field of regenerative medicine. Over the past 10 years CIRM has invested $904 million in “discovery stage/basic research”, and about $215 million in training grants that supported graduate students, post docs, clinical fellows, undergraduate, masters and high school students performing basic stem cell research. In the past couple of years, with only a limited amount of funds remaining, CIRM made a decision to invest most of the remaining funds into later stage projects, to support them through the difficult transition from bench to bedside. However, even now, CIRM continues to sponsor some basic research through its Bridges and SPARK Training Grant programs, where undergraduate, masters and even high school students are conducting stem cell research in world class stem cell laboratories, many of which are the same laboratories that were supported through CIRM basic research grants over the past 10 years. While basic stem cell research continues to receive a substantial level of support from the NIH ($1.8 billion in 2018, comprehensively on stem cell projects) and other funders, CIRM believes continued support for basic research, especially in key areas of stem cell research and vital opportunities, will always be important for discovering and developing new treatments.

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What is the future of the use of crispr cas9 in clinical trials in california/globally. Art Venegas

Dr. Kelly Shepard: CRISPR/Cas9 is a powerful gene editing tool. In only a few years, CRISPR/Cas9 technology has taken the field by storm and there are already a few CRISPR/Cas9 based treatments being tested in clinical trials in the US. There are also several new treatments that are at the IND enabling stage of development, which is the final testing stage required by the FDA before a clinical trial can begin. Most of these clinical trials involving CRISPR go through an “ex vivo” approach, taking cells from the patient with a disease causing gene, correcting the gene in the laboratory using CRISPR, and reintroducing the cells carrying the corrected gene back into the patient for treatment.  Sickle cell disease is a prime example of a therapy being developed using this strategy and CIRM funds two projects that are preparing for clinical trials with this approach.  CRISPR is also being used to develop the next generation of cancer T-cell therapies (e.g. CAR-T), where T-cells – a vital part of our immune system – are modified to target and destroy cancer cell populations.  Using CRISPR to edit cells directly in patients “in vivo” (inside the body) is far less common currently but is also being developed.  It is important to note that any FDA sanctioned “in vivo” CRISPR clinical trial in people will only modify organ-specific cells where the benefits cannot be passed on to subsequent generations. There is a ban on funding for what are called germ line cells, where any changes could be passed down to future generations.

CIRM is currently supporting multiple CRISPR/Cas9 gene editing projects in California from the discovery or most basic stage of research, through the later stages before applying to test the technique in people in a clinical trial.

While the field is new – if early safety signals from the pioneering trials are good, we might expect a number of new CRISPR-based approaches to enter clinical testing over the next few years. The first of these will will likely be in the areas of bone marrow transplant to correct certain blood/immune or  metabolic diseases, and cancer immunotherapies, as these types of approaches are the best studied and furthest along in the pipeline.

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Explain the differences between gene therapy and stem cell therapy? Renee Konkol

Dr. Stephen Lin:  Gene therapy is the direct modification of cells in a patient to treat a disease.  Most gene therapies use modified, harmless viruses to deliver the gene into the patient.  Gene therapy has recently seen many success in the clinic, with the first FDA approved therapy for a gene induced form of blindness in 2017 and other approvals for genetic forms of smooth muscle atrophy and amyloidosis. 

Stem cell therapy is the introduction of stem cells into patients to treat a disease, usually with the purpose of replacing damaged or defective cells that contribute to the disease.  Stem cell therapies can be derived from pluripotent cells that have the potential to turn into any cell in the body and are directed towards a specific organ lineage for the therapy.  Stem cell therapies can also be derived from other cells, called progenitors, that have the ability to turn into a limited number of other cells in the body. for example hematopoietic or blood stem cells (HSCs), which are found in bone marrow, can turn into other cells of the blood system including B-cells and T-cells: while mesenchymal stem cells (MSCs), which are usually found in fat tissue, can turn into bone, cartilage, and fat cells.  The source of these cells can be from the patient’s own body (autologous) or from another person (allogeneic).

Gene therapy is often used in combination with cell therapies when cells are taken from the patient and, in the lab, modified genetically to correct the mutation or to insert a correct form of the defective gene, before being returned to patients.  Often referred to as “ex vivo gene therapy” – because the changes are made outside the patient’s body – these therapies include Chimeric Antigen Receptor T (CAR-T) cells for cancer therapy and gene modified HSCs to treat blood disorders such as severe combined immunodeficiency and sickle cell disease. This is an exciting area that has significantly improved and even cured many people already.

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Currently, how can the outcome of CIRM stem cell medicine projects and clinical trials be soundly interpreted when their stem cell-specific doses are not known? James L. Sherley, M.D., Ph.D., Director. Asymmetrex, LLC

Dr. Stephen Lin:  Stem cell therapies that receive approval to conduct clinical trials must submit a package of data to the FDA that includes studies that demonstrate their effectiveness, usually in animal models of the disease that the cell therapy is targeting.  Those studies have data on the dose of the cell therapy that creates the therapeutic effect, which is used to estimate cell doses for the clinical trial.  CIRM funds discovery and translational stage awards to conduct these types of studies to prepare cell therapies for clinical trials.  The clinical trial is also often designed to test multiple doses of the cell therapy to determine the one that has the best therapeutic effect.   Dosing can be very challenging with cell therapies because of issues including survival, engraftment, and immune rejection, but CIRM supports studies designed to provide data to give the best estimate possible.

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Is there any research on using stem cells to increase the length of long bones in people?” For example, injecting stem cells into the growth plates to see if the cells can be used to lengthen limbs. Sajid

Dr. Kelly Shepard: There is quite a lot of ongoing research seeking ways to repair bones with stem cell based approaches, which is not the same but somewhat related. Much of this is geared towards repairing the types of bone injuries that do not heal well naturally on their own (large gaps, dead bone lesions, degenerative bone conditions). Also, a lot of this research involves engineering bone tissues in the lab and introducing the engineered tissue into a bone lesion that need be repaired. What occurs naturally at the growth plate is a complex interaction between many different cell types, much of which we do not fully understand. We do not fully understand how to use the cells that are used to engineer bone tissue in the lab. However, a group at Stanford, with some CIRM support, recently discovered a “skeletal stem cell” that exists naturally at the ends of human bones and at sites of fracture.  These are quite different than MSCs and offer a new path to be explored for repairing and generating bone. 

CIRM Board Awards $15.8 Million to Four Translational Research Projects

Last week, the CIRM Board approved $32.92 million in awards directed towards four new clinical trials in vision related diseases and Parkinson’s Disease.

In addition to these awards, the Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Before we go into more specific details of each one of these awards, here is a table summarizing these four new projects:

ApplicationTitleInstitutionAward Amount
TRAN1 11536Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome  UCLA $4,896,628
TRAN1 11555BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma  UCLA $3,176,805
TRAN1 11544 Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer  City of Hope $2,873,262
TRAN1 11611Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsyNeurona Therapeutics$4,848,750
Dr. Caroline Kuo, UCLA

$4.89 million was awarded to Dr. Caroline Kuo at UCLA to pursue a gene therapy approach for X-Linked Hyper IgM Syndrome (X-HIM).

X-HIM is a hereditary immune disorder observed predominantly in males in which there are abnormal levels of different types of antibodies in the body.  Antibodies are also known as Immunoglobulin (Ig) and they combat infections by attaching to germs and other foreign substances, marking them for destruction.  In infants with X-HIM, there are normal or high levels of antibody IgM but low levels of antibodies IgG, IgA, and IgE.  The low level of these antibodies make it difficult to fight off infection, resulting in frequent pneumonia, sinus infections, ear infections, and parasitic infections.  Additionally, these infants have an increased risk of cancerous growths. 

The gene therapy approach Dr. Kuo is continuing to develop involves using CRISPR/Cas9 technology to modify human blood stem cells with a functional version of the gene necessary for normal levels of antibody production.  The ultimate goal would be to take a patient’s own blood stem cells, modify them with the corrected gene, and reintroduce them back into the patient.

CIRM has previously funded Dr. Kuo’s earlier work related to developing this gene therapy approach for XHIM.

Dr. Yvonne Chen, UCLA

$3.17 million was awarded to Dr. Yvonne Chen at UCLA to develop a CAR-T cell therapy for multiple myeloma (MM).

MM is a type of blood cancer that forms in the plasma cell, a type of white blood cell that is found in the bone marrow.  An estimated 32,110 people in the United States will be diagnosed with MM in 2019 alone.  Several treatment options are available to patients with MM, but there is no curative therapy.

The therapy that Dr. Chen is developing will consist of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called a chimeric antigen receptor (CAR) that will recognize BCMA and CS1, two different markers found on the surface of MM cells.  These modified T cells (CAR-T cells) are then infused into the patient, where they are expected to detect and destroy BCMA and CS1 expressing MM cells.

Dr. Chen is using CAR-T cells that can detect two different markers in a separate clinical trial that you can read about in a previous blog post.

Dr. Karen Aboody, City of Hope

$2.87 million was awarded to Dr. Karen Aboody at City of Hope to develop an immunotherapy delivered via neural stem cells (NSCs) for treatment of ovarian cancer.

Ovarian cancer affects approximately 22,000 women per year in the United States alone.  Most ovarian cancer patients eventually develop resistance to chemotherapy, leading to cancer progression and death, highlighting the need for treatment of recurring ovarian cancer.

The therapy that Dr. Aboody is developing will use an established line of NSCs to deliver a virus that specifically targets these tumor cells.  Once the virus has entered the tumor cell, it will continuously replicate until the cell is destroyed.  The additional copies of the virus will then go on to target neighboring tumor cells.  This process could potentially stimulate the body’s own immune response to fight off the cancer cells as well.

Dr. Cory Nicholas, Neurona Therapeutics

$4.85 million was awarded to Dr. Cory Nicholas at Neurona Therapeutics to develop a treatment for epilepsy.

Epilepsy affects more than 3 million people in the United States with about 150,000 newly diagnosed cases in the US every year. It results in persistent, difficult to manage, or uncontrollable seizures that can be disabling and significantly impair quality of life. Unfortunately, anti-epileptic drugs fail to manage the disease in a large portion of people with epilepsy. Approximately one-third of epilepsy patients are considered to be drug-resistant, meaning that they do not adequately respond to at least two anti-epileptic drugs.

The therapy that Dr. Nicholas is developing will derive interneurons from human embryonic stem cells (hESCs). These newly derived interneurons would then be delivered to the brain via injection whereby the new cells are able to help regulate aberrant brain activity and potentially eliminate or significantly reduce the occurrence of seizures.

CIRM has previously funded the early stage development of this approach via a comprehensive grant and discovery grant.