Marathon effort to raise awareness about Huntington’s disease

The COVID pandemic put a lot of things on hold over the last two years. But thanks to the vaccine and boosters more and more people are feeling comfortable about getting out and about again. Case in point, the Orange County Marathon was held for the first time in two years on Sunday, May 1st.

Because May is Huntington’s disease Awareness Month the University of California at Irvine HD-CARE group took the opportunity to use the marathon to raise awareness about the disease, raise some money, but also to celebrate each other and the work they do.

Huntington’s disease is a particularly nasty disease. It’s a rare, inherited condition that leads to the steady breakdown of nerve cells in the brain, affecting movement and thinking and can cause severe psychiatric issues including mania and bipolar disorder. Treatments are limited and there is no cure.

Frances Saldana, a great supporter of CIRM and an amazing advocate for HD, told us they wanted the event to add friendship, hope, and fun in the lives of our scientists, patient advocates, and family members as we go together on our journey in search of a treatment and/or cure for Huntington’s disease. It was a really good day, and we had a lot of fun.” 

They created a short video to highlight just how much fun they had.

It’s a lovely reminder that even in the face of an horrendous disease like HD, people can find fellowship, fun and a sense of hope.

CIRM has invested almost $36 million in funds several projects targeting Huntington’s, and you can read about those here.

IBSC directors bring in nearly $12 million to fund the future of bimolecular research at UC Santa Cruz

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Left to right: Lindsay Hinck and Camilla Forsberg

UC Santa Cruz professors Camilla Forsberg and Lindsay Hinck are not only pushing boundaries in their field as the female-led program directors of the Institute for the Biology of Stem Cells (IBSC), they’ve also been looking for ways to enhance the environment within the academic research infrastructure.

“We really wanted to make an effort to elevate everyone’s capacity for doing more research,” explains Forsberg. It was this drive that led the researchers to focus on bringing in grants to support students at different stages of their education to participate in research training programs.

So far, Fosberg and Hinck’s efforts have provided nearly $12 million in extramural funding for predoctoral and undergraduate training programs. The California Institute for Regenerative Medicine (CIRM), which provides graduate and postdoctoral funding, is one of the five funding institutions that have supported IBSC. This funding will shape the future of the IBSC, which brings together more than 30 laboratories across the Engineering and Physical and Biological Sciences divisions, as well as the Science & Justice Research Center.

“We didn’t set out to have five training programs, but then there were more opportunities, so we kept pitching our basic mentoring philosophies to different funders,” Forsberg said. “Now we have five different programs. I guess we found a secret sauce that made our funders excited.”

Forsberg and Hinck’s secret sauce is perhaps in part due to their devotion to forming strong peer connections amongst a group of talented graduate and postdoctoral researchers. The programs aim to connect cohorts of trainees who can interact and network through the IBSC in order to form a peer support ecosystem.

Additionally, IBSC strives to build cohorts that welcome and foster diverse perspectives as they will host an upcoming pilot program that aims to demystify the lengthy path from academia to a research career.

With their lastest $1 million training grant from the National Institute of Child Health and Human Development (NICHD), Forsberg and Hinck hope to provide support for postdoctoral scholars interested in the biotech industry. So far, biotech companies Jasper Therapeutics and Roche have joined the collaborative effort with IBSC to create shadowing opportunities for trainees to learn outside of the academic environment.

Furthermore, pre and postdoctoral trainees supported by these training grants can be hosted by several labs in the IBSC and beyond.

“The key thing about all these training programs is that they implement new ideas about structured graduate and postdoctoral training,” Hinck said. “While getting a training grant position is competitive, we try to make the structured training provided by the grants widely available so that all graduate students and postdoctoral scholars at UCSC can increase their skill sets. The environment that’s built around these training programs elevates opportunities for everyone.”

Read the full release here.

UC Davis Health researchers aim to use CAR T cells for HIV cure

Dr. Abedi (right) in the lab at UC Davis Health. He and his team of researchers have launched a study looking to identify a potential cure for HIV. Photo Courtesy of UC Davis Health.

Worldwide, almost 38 million people are living with HIV—the virus that can lead to AIDS— and it’s estimated that 75% of them receive antiviral treatment to keep the virus in check. In California, 150,000 people live with HIV and 68% of these individuals are virally suppressed due to treatment.  

To fight this virus, UC Davis Health researchers—with funding from a CIRM grant—have launched a study looking to identify a potential cure for HIV. Using immunotherapy, researchers will take a patient’s own white blood cells, called T-cells, and modify them so that they can identify and target HIV cells to control the virus without medication. 

Targeting HIV with CAR T cells

“For this study we will educate the cells by inserting a gene to target cells that have been infected by the HIV virus,” explained Mehrdad Abedi, professor of internal medicine, hematology and oncology and the principal investigator of the study. “The idea is these modified cells will attach to the HIV-infected cells and destroy the cells that are infected while also stopping the infected cells’ ability to replicate.” 

Modified T-cells, known as CAR T cells, are an FDA-approved treatment for different forms of cancer including acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma. With cancer, the immune system often fails to deploy T-cells right away or at all. When it does, the attack is ineffective. CAR T-cell immunotherapy changes these collected T-cells to produce chimeric antigen receptors (or CARs) that adhere to tumors to destroy them. 

Study seeking HIV patients

For the study, UC Davis Health researchers are working to identify and recruit HIV-positive patients between the ages of 18 and 65 who have had an undetectable HIV viral load for the 12 months and have been on continuous antiretroviral therapy for at least 12 months.  

Patients also need to be willing to pause their antiretroviral therapy as part of the study. 

“While it is exciting, the study will require a lot of dedication from the patient because of the time commitment involved and the necessary steps required,” said Paolo Troia-Cancio, a clinical professor of medicine with the infectious disease division with over 20 years of experience treating HIV and co-investigator on the CAR T cell study.   

The search for an HIV cure 

Three patients have been cured of HIV using bone marrow transplants, including a woman in New York who received a cord blood stem cell transplant. She received a bone marrow transplant using umbilical cord blood donor cells that bore a mutation that makes them resistant to HIV infection to treat her leukemia. 

There have also been two previous cases involving an HIV cure following allogeneic bone marrow transplants. Both patients had leukemia and received bone marrow transplants from donors who carried the same mutation that blocks HIV infection.  

“While these stories provide inspiration and hope to finding a cure for HIV, a bone marrow transplant is not a realistic option for most patients,” said Abedi. “Such transplants are highly invasive and risky, so they are generally offered only to people with cancer who have exhausted all other options.” 

Abedi and his fellow researchers see this study as a potential road map to finding a cure for HIV.  

The California Institute for Regenerative Medicine (CIRM) has funded earlier work by Dr. Abedi and his team in trying to develop a therapy to help people with HIV who also have lymphoma.  

To read the source article about this CIRM-funded study, click here

Using reengineered human skin cells to treat COVID-19

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Investigators at Cedars-Sinai have identified a potential new therapy for COVID-19: a biologic substance created by reengineered human skin cells.   

In the study—co-funded by the California Institute for Regenerative Medicine (CIRM)—scientists found the substance stopped SARS-CoV-2, the virus that causes COVID-19, from reproducing itself. The substance also protected infected cells when tested in human lung cells.  

Although still in the early stages, the findings open the possibility of having a new therapy for COVID-19 patients, of which there are few. Current COVID-19 treatments primarily focus on preventing the virus from replicating. This new potential treatment inhibits replication but also protects or repairs tissue, which is important because COVID-19 can cause symptoms that affect patients long after the viral infection has been cleared. 

The potential therapy investigated in this study was created by scientists using skin cells called dermal fibroblasts. The investigators engineered the cells to produce therapeutic extracellular vesicles (EVs), which are nanoparticles that serve as a communication system between cells and tissue. Engineering these fibroblasts allowed them to secrete EVs—which the investigators dubbed “ASTEX”—with the ability to repair tissue. 

The study tested ASTEX by applying it to human lung epithelial cells, cells that line the pulmonary tract and are the targets of SARS-CoV-2 infection. They discovered that ASTEX prevented cells from launching an inflammatory process that could lead to cell death. Cells treated with ASTEX also made fewer of a type of protein called ACE that SARS-CoV-2 may use to infect cells. 

The team compared the new potential treatment with remdesivir, a drug currently used to treat COVID-19, and found that remdesivir did not inhibit production of ACE. Instead, remdesivir stops the virus from latching on to a protein called ACE2. ASTEX, therefore, may present another way to prevent the virus from entering cells. 

“We were surprised to find this potential therapy shuts down a novel pathway for viral replication and also protects infected cells,” said Ahmed G. Ibrahim, PhD, MPH, assistant professor in the Smidt Heart Institute at Cedars-Sinai and first author of the study. 

Investigators at Cedars-Sinai are planning future studies.  

The details of the potential therapy are published in the journal Biomaterials and Biosystems. Read the source article here

Rare Disease: An Uphill Battle for Diagnosis and Treatment

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From left to right: Baby Dalia pre-diagnosis, Dalia on her way to the kindergarten, and Dalia today.

When Dalia was 5 years old, she was finally diagnosed with MERRF syndrome– an extremely rare form of mitochondrial disease. By then, her parents had been searching for an answer for three frustrating years. And like most parents of a child suffering from an undiagnosed medical condition, they expected that Dalia’s diagnosis would start a path to recovery. 

Unfortunately for Dalia and millions of Americans who have a rare disease, the condition is chronic and life-threating. More than 90% of rare diseases have no treatment. None are curable. Even more heartbreaking for Dalia’s family, MERRF is degenerative. Time is of essence.

According to research published in The Journal of Rare Disorders, it takes seeing 7.3 physicians and trying for 4.8 years before getting an accurate rare disease diagnosis. This uphill battle aside, diagnosis is merely the first challenge. For the 7,000 known rare diseases, less than 600 have FDA-approved treatments.  

The irony of rare diseases is that a lot of people have them. The total number of Americans living with a rare disease is estimated at between 25-30 million. Two-thirds of these patients are children. “You feel alone, because by definition, your child’s diagnosis is exceptional. And yet, 1 in 10 Americans and 300 million people globally are living with a rare disease,” explains Jessica Fein, Dalia’s mother, in a heartfelt HuffPost article detailing her daughter’s diagnostic odyssey. 

For decades, the rare disease community has pointed to these staggering numbers to highlight that while individual diseases may be rare, the total number of people with a rare disease is large. 

In 1983, Congress passed the Orphan Drug Act in order to provide incentives for drug companies to develop treatments for rare diseases. Between 1973 and 1983, fewer than 10 treatments for rare diseases were approved. Since 1983, hundreds of drugs and biologic products for rare diseases have been approved by the FDA. While researchers have made progress in learning how to diagnose, treat, and even prevent a variety of rare diseases, there is still much to do because like Dalia, most patients living with a rare disorder have no treatments to even consider. 

Four years after her diagnosis, Dalia lost her ability to walk, talk, eat, and breathe without a ventilator. At the time she was only 9 years old. More than a decade after her diagnosis, Dalia is finally enrolled in a clinical trial. Her parents hope that awareness about rare diseases and their prevalence will lead to research, funding, advocacy and health equity. 

Here at the California Institute for Regenerative Medicine (CIRM), we understand the importance of funding research that impacts not just the most common diseases. In fact, more than one third of all the projects we fund target a rare disease or condition such as: Retinitis pigmentosa, Sickle cell disease, Huntington’s disease, and Duchenne Muscular Dystrophy.

“[If] each of us learned a bit about just one rare disease… it probably wouldn’t change the trajectory for most of the people who are currently suffering, but it might help someone be diagnosed earlier. We’ve made leaps and bounds with awareness, research and treatment for AIDS, cancer and depression, all diseases that were once unknown… Awareness and action aren’t things that can be put on the back burner until more common illnesses are cured. We must do what we can today- and every day moving forward.”

How two California researchers are advancing world class science to develop real life solutions

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In our recently launched 5-year Strategic Plan, the California Institute for Regenerative Medicine (CIRM) profiled two researchers who have leveraged CIRM funding to translate basic biological discoveries into potential real-world solutions for devastating diseases.

Dr. Joseph Wu is director of the Stanford Cardiovascular Institute and the recipient of several CIRM awards. Eleven of them to be exact! Over the past 10 years, Dr. Wu’s lab has extensively studied the application of induced pluripotent stem cells (iPSCs) for cardiovascular disease modeling, drug discovery, and regenerative medicine. 

Dr. Wu’s extensive studies and findings have even led to a cancer vaccine technology that is now being developed by Khloris Biosciences, a biotechnology company spun out by his lab. 

Through CIRM funding, Dr. Wu has developed a process to produce cardiomyocytes (cardiac muscle cells) derived from human embryonic stem cells for clinical use and in partnership with the agency. Dr. Wu is also the principal investigator in the first-in-US clinical trial for treating ischemic heart disease. His other CIRM-funded work has also led to the development of cardiomyocytes derived from human induced pluripotent stem cells for potential use as a patch.

Over at UCLA, Dr. Lili Yang and her lab team have generated invariant Natural Killer T cells (iNKT), a special kind of immune system cell with unique features that can more effectively attack tumor cells. 

More recently, using stem cells from donor cord-blood and peripheral blood samples, Dr. Yang and her team of researchers were able to produce up to 300,000 doses of hematopoietic stem cell-engineered iNKT (HSC–iNKT) cells. The hope is that this new therapy could dramatically reduce the cost of producing immune cell products in the future. 

Additionally, Dr. Yang and her team have used iNKT cells to develop both autologous (using the patient’s own cells), and off-the-shelf anti-cancer therapeutics (using donor cells), designed to target blood cell cancers.

The success of her work has led to the creation of a start-up company called Appia Bio. In collaboration with Kite Pharma, Appia Bio is planning on developing and commercializing the promising technology. 

CIRM has been an avid supporter of Dr. Yang and Dr. Wu’s research because they pave the way for development of next-generation therapies. Through our new Strategic Plan, CIRM will continue to fund innovative research like theirs to accelerate world class science to deliver transformative regenerative medicine treatments in an equitable manner to a diverse California and the world.

Visit this page to learn more about CIRM’s new 5-year Strategic Plan and stay tuned as we share updates on our 5-year goals here on The Stem Cellar.

Researchers develop a stem cell-based implant for cartilage restoration and treating osteoarthritis

The Plurocart’s scaffold membrane seeded with stem cell-derived chondrocytes. Image courtesy of USC Photo/Denis Evseenko.

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Researchers at the Keck School of Medicine of USC have used a stem cell-based bio-implant to repair cartilage and delay joint degeneration in a large animal model. This paves the way to potentially treat humans with cartilage injuries and osteoarthritis, which occurs when the protective cartilage at the ends of the bones wears down over time. The disorder affects millions worldwide.

 The researchers are using this technology to manufacture the first 64 implants to be tested on humans with support from a $6 million grant from the California Institute for Regenerative Medicine (CIRM).

Researchers Dr. Denis Evseenko, and Dr. Frank Petrigliano led the development of the therapeutic bio-implant, called Plurocart. It’s composed of a scaffold membrane seeded with stem cell-derived chondrocytes, the cells responsible for producing and maintaining healthy articular cartilage tissue. 

In the study, the researchers implanted the Plurocart membrane into a pig model of osteoarthritis, resulting in the long-term repair of articular cartilage defects. Evseenko said the findings are significant because the implant fully integrated in the damaged articular cartilage tissue and survived for up to six months. “Previous studies have not been able to show survival of an implant for such a long time,” Evseenko added.

The researchers also found that the cartilage tissue generated was strong enough to withstand compression and elastic enough to accommodate movement without breaking.

Osteoarthritis, an often-painful disorder, can affect any joint, but most commonly affects those in our knees, hips, hands and spine. The USC researchers hope their implant will help prevent the development of arthritis and alleviate the need for invasive joint replacement surgeries.

“Many of the current options for cartilage injury are expensive, involve complex logistical planning, and often result in incomplete regeneration,” said Petrigliano. “Plurocart represents a practical, inexpensive, one-stage therapy that may be more effective in restoring damaged cartilage and improve the outcome of such procedures.”

Read the full study here and learn more about the CIRM grant here.

Sweating bullets and other stories from the front line

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When the COVID-19 pandemic hit and the 2020 election became one of the most contentious in living history it suddenly made trying to get a proposition on the ballot in California a lot harder. That meant the fate of Proposition 14, a ballot initiative refunding CIRM, California’s Stem Cell Agency, was in doubt. And if the agency went down, then a vital source of future funding for scientific research that could change and even save lives would also disappear.

It was a pretty nerve-racking time for all of us involved. We waited day after day after day after day before the election was finally called. Happily, it was in our favor. But only just!

In this podcast we talk to two of the key figures in this saga. Melissa King and Maria Bonneville. Melissa was part of the team that helped secure the votes needed to pass Proposition 14, and Maria helped keep CIRM on track to cope with whatever the outcome of the election was. 

I hope you enjoy this latest episode of our podcast ‘Talking ‘Bout (re)Generation.’

Building a better brain (model) in the lab

Leica Picture of a brain organoid: courtesy National Institute of Allergy and Infectious Diseases, NIH

One of the biggest problems with trying to understand what is happening in a disease that affects the brain is that it’s really difficult to see what is going on inside someone’s head. People tend to object to you trying to open their noggin while they are still using it.

New technologies can help, devices such as MRI’s – which chart activity and function by measuring blood flow – or brain scans using electroencephalograms (EEGs), which measure activity by tracking electrical signaling and brain waves. But these are still limited in what they can tell us.

Enter brain organoids. These are three dimensional models made from clusters of human stem cells grown in the lab. They aren’t “brains in a dish” – they can’t function or think independently – but they can help us develop a deeper understanding of how the brain works and even why it doesn’t always work as well as we’d like.

Now researchers at UCLA’s Broad Center of Regenerative Medicine have created brain organoids that demonstrate brain wave activity similar to that found in humans, and even brain waves found in particular neurological disease.

The team – with CIRM funding – took skin tissue from healthy individuals and, using the iPSC method – which enables you to turn these cells into any other kind of cell in the body – they created brain organoids. They then studied both the physical structure of the organoids by examining them under a microscope, and how they were functioning by using a probe to measure brain wave activity.

In a news release Dr. Ranmal Samarasinghe, the first author of the study in the journal Nature Neuroscience, says they wanted to do this double test for a very good reason: “With many neurological diseases, you can have terrible symptoms but the brain physically looks fine. So, to be able to seek answers to questions about these diseases, it’s very important that with organoids we can model not just the structure of the brain but the function as well.”

Next, they took skin cells from people with a condition called Rhett syndrome. This is a rare genetic disorder that affects mostly girls and strikes in the first 18 months of life, having a severe impact on the individual’s ability to speak, walk, eat or even breathe easily. When the researchers created brain organoids with these cells the structure of the organoids looked similar to the non-Rhett syndrome ones, but the brain wave activity was very different. The Rhett syndrome organoids showed very erratic, disorganized brain waves.

When the team tested an experimental medication called Pifithrin-alpha on the Rhett organoids, the brain waves became less erratic and more like the brain waves from the normal organoids.

“This is one of the first tangible examples of drug testing in action in a brain organoid,” said Samarasinghe. “We hope it serves as a stepping stone toward a better understanding of human brain biology and brain disease.”

We’ve got cash, here’s how you can get some

When the voters of California approved Proposition 14 last November (thanks folks) they gave us $5.5 billion to continue the work we started way back in 2014. It’s a great honor, and a great responsibility.

It’s also a great opportunity to look at what we do and how we do it and try to come up with even better ways of funding groundbreaking research and helping create a new generation of researchers.

In addition to improving on what we already do, Prop 14 introduced some new elements, some new goals for us to add to the mix, and we are in the process of fleshing out how we can best do that.

Because of all these changes we decided it would be a good idea to hold a “Town Hall” meeting and let everyone know what these changes are and how they may impact applications for funding.

The Town Hall, on Tuesday June 29, was a great success with almost 200 participants. But we know that not everyone who wanted to attend could, so here’s the video of the event, and below that are the questions that were posed by people during the meeting, and the answers to those questions.

Having seen the video we would be eternally grateful if you could respond to a short online survey, to help us get a better idea of your research and education needs and to be better able to serve you and identify potential areas of opportunity for CIRM. Here’s a link to that survey: https://www.surveymonkey.com/r/VQMYPDL

We know that there may be issues or questions that are not answered here, so feel free to send those to us at info@cirm.ca.gov and we will make sure you get an answer.

Are there any DISC funding opportunities specific to early-stage investigators?

DISC funding opportunities are open to all investigators.  There aren’t any that are specific to junior investigators.

Are DISC funding opportunities available for early-mid career researchers based out of USA such as Australia?

Sorry, you have to be in California for us to fund your work.

Does tumor immunology/ cancer immunotherapy fall within the scope of the CIRM discovery grants?

Yes, they do.  Here is a link to various CIRM DISC Awards that fall within the cancer category.  https://www.cirm.ca.gov/grants?disease_focus%5B%5D=1427&program_type%5B%5D=1230

Will Disc1 (Inception awards) and/or seed funding mechanisms become available again?

CIRM is anticipating launching a program to meet this need toward the end of this year.

For DISC award is possible to contact a grant advisor for advice before applying?

Please email discovery@cirm.ca.gov to discuss Discovery stage applications before applying

Is co-funding requirement a MUST for clinical trials?

Co-funding requirements vary.  Please refer to the following link for more information: https://www.cirm.ca.gov/sites/default/files/files/about_cirm/CLIN2_Mini_Brochure2.pdf

Hi, when will reviews for DISC 2: CIRM Quest – Discovery Stage Research Projects (deadline March 2021) be available? Thanks!

Review summaries for the March 2021 Discovery submitted applications will be available by mid-August, with final board funding decisions at the August 24th Application Review Subcommittee Meeting

Has CIRM project made it to Phase III or product launch with FDA approval? What is CIRM strategy for start-up biotech companies?

CIRM has funded several late-stage Phase III/potentially pivotal clinical trials. You can view them here: https://www.cirm.ca.gov/our-impact/funding-clinical-trials

CIRM funding supports non-profit academic grantees as well as companies of all sizes.

I am studying stem cells using mouse. Is my research eligible for the CIRM grants?

Yes it is.

Your programs more specifically into stem cell research would be willing to take patients that are not from California?

Yes, we have treated patients who are not in California. Some have come to California for treatment and others have been treated in other states in the US by companies that are based here in California.

Can you elaborate how the preview of the proposals works? Who reviews them and what are the criteria for full review?

The same GWG panel both previews and conducts the full review. The panel first looks through all the applications to identify what each reviewer believes represents the most likely to be impactful and meet the goals of the CIRM Discovery program. Those that are selected by any reviewer moves forward to the next full review step.

If you meet your milestones-How likely is it that a DISC recipient gets a TRAN award?

The milestones are geared toward preparation of the TRAN stage.  However, this is a different application and review that is not guaranteed to result in funding.

Regarding Manufacturing Public Private partnerships – What specific activities is CIRM thinking about enabling these partnerships? For example, are out of state for profit commercial entities able to conduct manufacturing at CA based manufacturing centers even though the clinical program may be primarily based out of CA? If so, what percent of the total program budget must be expended in CA? How will CIRM enable GMP manufacturing centers interact with commercial entities?

We are in the early stages of developing this concept with continued input from various stakeholders. The preliminary vision is to build a network of academic GMP manufacturing centers and industry partners to support the manufacturing needs of CIRM-funded projects in California.

We are in the process of widely distributing a summary of the manufacturing workshop. Here’s a link to it:

If a center is interested in being a sharing lab or competency hub with CIRM, how would they go about it?

CIRM will be soliciting applications for Shared Labs/Competency hubs in potential future RFAs. The survey asks several questions asking for feedback on these concepts so it would really help us if you could complete the survey.

Would preclinical development of stem cell secretome-derived protein therapies for rare neuromuscular diseases and ultimately, age-related muscle wasting be eligible for CIRM TRAN1 funding? The goal is to complete IND-enabling studies for a protein-based therapy that enhances tissue regeneration to treat a rare degenerative disease. the screening to identify the stem-cell secreted proteins to develop as therapeutics is done by in vitro screening with aged/diseased primary human progenitor cells to identify candidates that enhance their differentiation . In vivo the protein therapeutic signals to several cell types , including precursor cells to improve tissue homeostasis.

I would suggest reaching out to our Translation team to discuss the details as it will depend on several factors. You can email the team at translational@cirm.ca.gov

Here are the slides used in the presentations.