Partners in health

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

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

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

Gene therapy research at UC Davis

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

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

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

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

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

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

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

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

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

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

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

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

.Joseph Anderson

Joseph Anderson

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

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

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

Kyle David Fink

Kyle David Fink

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

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

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

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

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

Developing potential lifetime cures

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

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

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

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

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

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

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

Exploring tough questions, looking for answers

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

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

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

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

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

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

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

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

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

Explaining COVID can be a pitch

When people ask me what I do at CIRM I sometimes half-jokingly tell them that I’m the official translator: I take complex science and turn it into everyday English. That’s important. The taxpayers of California have a right to know how their money is being spent and how it might benefit them. But that message can be even more effective when it comes from the scientists themselves.

Recently we asked some of the scientists we are funding to do research into COVID-19 to record what’s called an “elevator pitch”. This is where they prepare an explanation of their work that is in ordinary English and is quite short, short enough to say it to someone as you ride in an elevator. Hence the name.

It sounds easy enough. But it’s not. When you are used to talking in the language of science day in and day out, suddenly switching codes to talk about your work in plain English can take some practice. Also, you have spent years, often decades, on this work and to have to explain it in around one minute is no easy thing.

But our researchers rose to the challenge. Here’s some examples of just how well they did.

It’s all about the patients

Ronnie, born with a fatal immune disorder now leading a normal life thanks to a CIRM-funded stem cell/gene therapy: Photo courtesy of his mum Upasana

Whenever you are designing something new you always have to keep in mind who the end user is. You can make something that works perfectly fine for you, but if it doesn’t work for the end user, the people who are going to work with it day in and day out, you have been wasting your time. And their time too.

At CIRM our end users are the patients. Everything we do is about them. Starting with our mission statement: to accelerate stem cell treatments to patients with unmet medical needs. Everything we do, every decision we make, has to keep the needs of the patient in mind.

So, when we were planning our recent 2020 Grantee Meeting (with our great friends and co-hosts UC Irvine and UC San Diego) one of the things we wanted to make sure didn’t get lost in the mix was the face and the voice of the patients. Often big conferences like this are heavy on science with presentations from some of the leading researchers in the field. And we obviously wanted to make sure we had that element at the Grantee meeting. But we also wanted to make sure that the patient experience was front and center.

And we did just that. But more on that in a minute. First, let’s talk about why the voice of the patient is important.

Some years ago, Dr. David Higgins, a CIRM Board member and patient advocate for Parkinson’s Disease (PD), said that when researchers are talking about finding treatments for PD they often focus on the dyskinesia, the trembling and shaking and muscle problems. However, he said if you actually asked people with PD you’d find they were more concerned with other aspects of the disease, the insomnia, anxiety and depression among other things. The key is you have to ask.

Frances Saldana, a patient advocate for research into Huntington’s disease

So, we asked some of our patient advocates if they would be willing to be part of the Grantee Meeting. All of them, without hesitation, said yes. They included Frances Saldana, a mother who lost three of her children to Huntington’s disease; Kristin MacDonald, who lost her sight to a rare disorder but regained some vision thanks to a stem cell therapy and is hoping the same therapy will help restore some more; Pawash Priyank, whose son Ronnie was born with a fatal immune disorder but who, thanks to a stem cell/gene therapy treatment, is now healthy and leading a normal life.

Because of the pandemic everything was virtual, but it was no less compelling for that. We interviewed each of the patients or patient advocates beforehand and those videos kicked off each session. Hearing, and seeing, the patients and patient advocates tell their stories set the scene for what followed. It meant that the research the scientists talked about took on added significance. We now had faces and names to highlight the importance of the work the scientists were doing. We had human stories. And that gave a sense of urgency to the work the researchers were doing.

But that wasn’t all. After all the video presentations each session ended with a “live” panel discussion. And again, the patients and patient advocates were a key part of that. Because when scientists talk about taking their work into a clinical trial they need to know if the way they are setting up the trial is going to work for the patients they’re hoping to recruit. You can have the best scientists, the most promising therapy, but if you don’t design a clinical trial in a way that makes it easy for patients to be part of it you won’t be able to recruit or retain the people you need to test the therapy.

Patient voices count. Patient stories count.

But more than anything, hearing and seeing the people we are trying to help reminds us why we do this work. It’s so easy to get caught up in the day to day business of our jobs, struggling to get an experiment to work, racing to get a grant application in before the deadline. Sometimes we get so caught up in the minutiae of work we lose sight of why we are doing it. Or who we are doing it for.

At CIRM we have a saying; come to work every day as if lives depend on you, because lives depend on you. Listening to the voices of patients, seeing their faces, hearing their stories, reminds us not to waste a moment. Because lives depend on all of us.

Here’s one of the interviews that was featured at the event. I do apologize in advance for the interviewer, he’s rubbish at his job.

CIRM-funded kidney transplant procedure eyeing faster approval

Kidney transplant surgery.

Medeor Therapeutics, which is running a CIRM-funded clinical trial to help people getting kidney transplants, just got some really good news. The US Food and Drug Administration (FDA) has just granted their product Regenerative Medicine Advanced Therapy (RMAT) designation. That’s a big deal because it means they may be able to apply for faster review and approval and get their therapy to more patients faster.

Here’s why that RMAT designation matters.

Over 650,000 Americans suffer from end-stage kidney disease – a life-threatening condition caused by the loss of kidney function. The best available treatment for these patients is a kidney transplant from a genetically matched living donor. However, patients who receive a transplant must take life-long immunosuppressive drugs to prevent their immune system from rejecting the transplanted organ. Over time, these drugs are toxic and can increase a patient’s risk of infection, heart disease, cancer and diabetes.  Despite these drugs, many patients still lose transplanted organs due to rejection.

To tackle this problem Medeor is developing a stem cell-based therapy called MDR-101. This is being tested in a Phase 3 clinical trial and it’s hoped it will eliminate the need for immunosuppressive drugs in genetically matched kidney transplant patients.

The company takes blood-forming stem cells and immune cells from the organ donor and infuses them into the patient receiving the donor’s kidney. Introducing the donor’s immune cells into the patient creates a condition called “mixed chimerism” where immune cells from the patient and the donor are able to co-exist. In this way, the patient’s immune system is able to adapt to and tolerate the donor’s kidney, potentially eliminating the need for the immunosuppressive drugs that are normally necessary to prevent transplant rejection.

So how does getting RMAT designation help that? Well, the FDA created the RMAT program to help speed up the development and review of regenerative medicine therapies that can treat, modify, reverse, or cure a serious condition. If MDR-101shows it is both safe and effective RMAT could help it get faster approval for wider use.

In a news release Giovanni Ferrara, President and CEO of Medeor, welcomed the news.

“This important designation underscores the tremendous unmet medical need for alternatives to today’s immunosuppressive therapies for transplantation. We have the potential to help people live longer, healthier lives without the need for high dose and chronic immunosuppression and we thank the FDA for this designation that will assist us progressing as efficiently as possible toward a commercially available product.”

This is the seventh CIRM-supported project that has been granted RMAT designation. The others are jCyte, Lineage, Humacyte, St. Jude’s/UCSF X-linked SCID, Poseida, Capricor

Charting a new course for stem cell research

What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.

Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.

The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?

It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.

We’ll hear what’s being done to find therapies for

  • Rare diseases that affect children
  • Type 1 diabetes
  • HIV/AIDS
  • Glioblastoma
  • Multiple myeloma

We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.

It’s going to be a fascinating day. And did I mention it’s free!

All you have to do is go to this Eventbrite page to register.

And feel free to share this with your family, friends or anyone you think might be interested.

We look forward to seeing you there.

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.

CIRM joins forces with US Department of Defense to fight COVID

Photo courtesy of Gabrielle Lurie / San Francisco Chronicle / Polaris

Small state agencies like CIRM don’t normally get to partner with a behemoth like the Department of Defense (DOD), but these are not normal times. Far from it. That’s why we are both joining forces with the National Institutes of Health to fund a clinical trial that hopes to help patients on a ventilator battling a sometime fatal condition that attacks their lungs.

The study is being run by Dr. Michael Matthay from U.C. San Francisco. CIRM awarded Dr. Matthay $750,000 to help expand an existing trial and to partner with U.C. Davis to bring in more patients, particularly from underserved communities.

This approach uses mesenchymal stem cells (MSCs) taken from bone marrow to help patients with a condition called acute respiratory distress syndrome (ARDS). This occurs when the virus attacks the lungs.

In an article in UCSF News, Dr. Matthay says the impact can be devastating.

“Tiny air spaces in the lungs fill up with fluid and prevent normal oxygen uptake in the lungs. That’s why the patient has respiratory failure. Usually these patients have to be intubated and treated with a mechanical ventilator.”

Many patients don’t survive. Dr. Matthay estimates that as many as 60 percent of COVID-19 patients who get ARDS die.

This is a Phase 2 double blind clinical trial which means that half the 120 patients who are enrolled will get MSCs (which come from young, health donors) and the other half will get a placebo. Neither the patients getting treated nor the doctors and nurses treating them will know who gets what.

Interestingly this trial did not get started as a response to COVID-19. In fact, it’s the result of years of work by Dr. Matthay and his team hoping to see if MSC’s could help people who have ARDs as a result of trauma, bacterial or other infection. They first started treating patients earlier this year when most people still considered the coronavirus a distant threat.

“We started the study in January 2020, and then COVID-19 hit, so we have been enrolling patients over the last eight months. Most of the patients we’ve enrolled in the trial have ended up having severe viral pneumonia from COVID.”

So far CIRM has funded 17 different projects targeting COVID-19. You can read about those in our Press Release section.

CIRM partners with UCLA scientists to take on COVID-19

Don’t you love it when someone does your job for you and does it so well you have no need to add anything to it! Doesn’t happen very often – sad to say – but this week our friends at UCLA wrote a great article describing the work they are doing to target COVID-19. Best of all, all the work described is funded by CIRM. So read, and enjoy.

Two scientists in a lab at the UCLA Broad Stem Cell Research Center

By Tiare Dunlap, UCLA

As the COVID-19 pandemic rages on, UCLA researchers are rising to the occasion by channeling their specialized expertise to seek new and creative ways to reduce the spread of the virus and save lives. Using years’ — or even decades’ — worth of knowledge they’ve acquired studying other diseases and biological processes, many of them have shifted their focus to the novel coronavirus, and they’re collaborating across disciplines as they work toward new diagnostic tests, treatments and vaccines.

At UCLA, more than 230 research projects, including several being led by members of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, are contributing to that mission.

Dr. Brititte Gomperts, Photo courtesy UCLA

“As a result of the pandemic, everyone on campus is committed to finding ways that their unique expertise can help out,” said Dr. Brigitte Gomperts, professor and vice chair of research in pediatric hematology-oncology and pulmonary medicine at the David Geffen School of Medicine at UCLA and a member of the UCLA Children’s Discovery and Innovation Institute. “So many of my colleagues have repurposed their labs to work on the virus. It’s very seldom that you have one thing that everybody’s working on, and it has been truly inspiring to see how everyone has come together to try and solve this.”

Here’s a look at five projects in which UCLA scientists are using stem cells — which can self-replicate and give rise to all cell types — to take on COVID-19.

Using lung organoids as models to test possible treatments 

Dr. Brigitte Gomperts

Gomperts has spent years perfecting methods for creating stem cell–derived three-dimensional lung organoids. Now, she’s using those organoids to study how SARS-CoV-2, the virus that causes COVID-19, affects lung tissue and to rapidly screen thousands of prospective treatments. Because the organoids are grown from human cells and reflect the cell types and architecture of the lungs, they can offer unprecedented insights into how the virus infects and damages the organ.  

Gomperts is collaborating with UCLA colleagues Vaithilingaraja Arumugaswami, a virologist, and Robert Damoiseaux, an expert in molecular screening. Their goal is to find an existing therapy that could be used to reduce the spread of infection and associated damage in the lungs.

“We’re starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible,” Gomperts said. Read more.

Repurposing a cancer therapy

Dr. Vaithi Arumugaswami: Photo courtesy UCLA

Vaithilingaraja Arumugaswami, associate professor of molecular and medical pharmacology at the Geffen School of Medicine

In addition to collaborating with Gomperts, Arumugaswami and Damoiseaux identified the cancer drug Berzosertib as a possible treatment for COVID-19 after screening 430 drug candidates. The drug, which is currently being tested in clinical trials for cancer, works by blocking a DNA repair process that is exploited by solid cancers and the SARS-CoV-2 virus, and the UCLA scientists found that it is very effective at limiting viral replication and cell death. 

“Clinical trials have shown that Berzosertib blocks the DNA repair pathway in cancer cells, but has no effects on normal, healthy cells,” Arumugaswami said.

Now, Arumugaswami and Gustavo Garcia Jr., a staff research associate, are testing Berzosertib and additional drug combinations on lung organoids developed in Gomperts’ lab and stem cell–derived heart cells infected with SARS-CoV-2. They suspect that if the drug is administered soon after diagnosis, it could limit the spread of infection and prevent complications. Read more.

Studying the immune response to the virus

Dr. Gay Crooks

Dr. Gay Crooks, professor of pathology and laboratory medicine and of pediatrics at the Geffen School of Medicine, and co-director of the Broad Stem Cell Research Center; and Dr. Christopher Seet,  

assistant professor of hematology-oncology at the Geffen School of Medicine

Crooks and Seet are using stem cells to model how immune cells recognize and fight the virus in a lab dish. To do that, they’re infecting blood-forming stem cells — which can give rise to all blood and immune cells — from healthy donors with parts of the SARS-CoV-2 virus and then coaxing the stem cells to produce immune cells called dendritic cells. Dendritic cells devour viral proteins, chop them up into pieces and then present those pieces to other immune cells called T cells to provoke a response.

By studying that process, Crooks and Seet hope to identify which parts of the virus provoke the strongest T-cell responses. Developing an effective vaccine for SARS-CoV-2 will require a deep understanding of how the immune system responds to the virus, and this work could be an important step in that direction, giving researchers and clinicians a way to gauge the effectiveness of possible vaccines.

“When we started developing this project some years ago, we had no idea it would be so useful for studying a viral infection — any viral infection,” Crooks said. “It was only because we already had these tools in place that we could spring into action so fast.” Read more.

Developing a booster that could help a vaccine last longer

Song Li, chair and professor of bioengineering at the UCLA Samueli School of Engineering

A COVID-19 vaccine will need to provide long-term protection from infection. But how long a vaccine protects from infection isn’t solely dependent on the vaccine.

The human body relies on long-living immune cells called T memory stem cells that guard against pathogens such as viruses and bacteria that the body has encountered before. Unfortunately, the body’s capacity to form T memory stem cells decreases with age. So no matter how well designed a vaccine is, older adults who don’t have enough of a response from T memory stem cells will not be protected long-term.

To address that issue, Li is developing an injectable biomaterial vaccine booster that will stimulate the formation of T memory stem cells. The booster is made up of engineered materials that release chemical messengers to stimulate the production of T memory stem cells. When combined with an eventual SARS-CoV-2 vaccine, they would prompt the body to produce immune cells primed to recognize and eliminate the virus over the long term.

“I consider it my responsibility as a scientist and an engineer to translate scientific findings into applications to help people and the community,” Li said. Read more.

Creating an off-the-shelf cell therapy

Lili Yang, associate professor of microbiology, immunology and molecular genetics in the UCLA College

Invariant natural killer T cells, or iNKT cells, are the special forces of the immune system. They’re extremely powerful and can immediately recognize and respond to many different intruders, from infections to cancer.

Yang is testing whether iNKT cells would make a particularly effective treatment for COVID-19 because they have the capacity to kill virally infected cells, offer protection from reinfection and rein in the excessive inflammation caused by a hyperactive immune response to the virus, which is thought to be a major cause of tissue damage and death in people with the disease.

One catch, though, is that iNKT cells are incredibly scarce: One drop of human blood contains around 10 million blood cells but only around 10 iNKT cells. That’s where Yang’s research comes in. Over the past several years, she has developed a method for generating large numbers of iNKT cells from blood-forming stem cells. While that work was aimed at creating a treatment for cancer, Yang’s lab has adapted its work over the past few months to test how effective stem cell–derived iNKT cells could be in fighting COVID-19. With her colleagues, she has been studying how the cells work in fighting the disease in models of SARS-CoV-2 infection that are grown from human kidney and lung cells.

“My lab has been developing an iNKT cell therapy for cancer for years,” Yang said. “This means a big part of the work is already done. We are repurposing a potential therapy that is very far along in development to treat COVID-19.” Read more.

“Our center is proud to join CIRM in supporting these researchers as they adapt projects that have spent years in development to meet the urgent need for therapies and vaccines for COVID-19,” said Dr. Owen Witte, founding director of the UCLA Broad Stem Cell Research Center. “This moment highlights the importance of funding scientific research so that we may have the foundational knowledge to meet new challenges as they arise.” Crooks, Gomperts, Seet and Yang are all members of the UCLA Jonsson Comprehensive Cancer Center. Damoiseaux is a professor of molecular and medical pharmacology and director of the Molecular Shared Resource Center at the California NanoSystems Institute at UCLA