Precision guided therapy from a patient’s own cells

Dr. Wesley McKeithan, Stanford

Imagine having a tool you could use to quickly test lots of different drugs against a disease to see which one works best. That’s been a goal of stem cell researchers for many years but turning that idea into a reality hasn’t been easy. That may be about to change.

A team of CIRM-funded researchers at the Stanford Cardiovascular Institute and the Human BioMolecular Research Institute in San Diego found a way to use stem cells from patients with a life-threatening heart disease, to refine an existing therapy to make it more effective, with fewer side effects.

The disease in question is called long QT syndrome (LQTS). This is a heart rhythm condition that can cause fast, chaotic heartbeats. Some people with the condition have seizures. In some severe cases, particularly in younger people, LQTS can cause sudden death.

There are a number of medications that can help keep LQTS under control. One of these is mexiletine. It’s effective at stabilizing the heart’s rhythm, but it also comes with some side effects such as stomach pain, chest discomfort, drowsiness, headache, and nausea.

The team wanted to find a way to test different forms of that medication to see if they could find one that worked better and was safer to take. So they used induced pluripotent stem cells (iPSCs) from patients with LQTS to do just that.

iPSCs are cells that are made from human tissue – usually skin – that can then be turned into any other cell in the body. In this case, they took tissue from people with LQTS and then turned them into heart cells called cardiomyocytes, the kind affected by the disease. The beauty of this technique is that even though these cells came from another source, they now look and act like cardiomyocytes affected by LQTS.

Dr. Mark Mercola, Stanford

In a news release Stanford’s Dr. Mark Mercola, the senior author of the study, said using these kinds of cells gave them a powerful tool.

“Drugs for heart disease are typically developed using overly simplified models, like tumor cells engineered in a specific way to mimic a biochemical event. Consequently, drugs like this one, mexiletine, have undesirable properties of concern in treating patients. Here, we used cells from a patient to generate that person’s heart muscle cells in a dish so we could visualize both the good and bad effects of the drug.”

The researchers then used these man-made cardiomyocytes to test various drugs that were very similar in structure to mexiletine. They were looking for ones that could help stabilize the heart arrhythmia but didn’t produce the unpleasant side effects. And they found some promising candidates.

Study first author, Dr. Wesley McKeithan, says the bigger impact of the study is that they were able to show how this kind of cell from patients with a particular disease can be used to “guide drug development and identify better drug improvement and optimization in a large-scale manner.”

 “Our approach shows the feasibility of introducing human disease models early in the drug development pipeline and opens the door for precision drug design to improve therapies for patients.”

The study is published in the journal Cell Stem Cell.

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.

Researchers discover how to steer stem cells to regenerate cartilage in joints

Dr. Charles K.F. Chan (Left) and Dr. Michael Longaker (right), Stanford University

Cartilage is a flexible, connective tissue in our joints that is important for cushioning our bones against impacts. This cartilage deteriorates as we age due to normal wear and tear and in some instances excessive damage or a deteriorating disease. The deterioration of cartilage is also the primary cause of joint pain and arthritis, which affects more than 55 million Americans.

It was generally assumed that adult cartilage could not be regenerated after damage. Fortunately, a CIRM funded project by Dr. Charles K.F. Chan, Dr. Michael Longaker, and Dr. Matthew Murphy at Stanford University found a way to use chemical signals to steer skeletal stem cells, which are responsible for the production of bone and cartilage, to regrow cartilage in joints.

Damaged cartilage is currently treated with a technique known as microfracture. Tiny holes are drilled into the surface of a joint, which activates the body’s skeletal stem cells to create fibrocartilage in the joint. Unfortunately, this newly created tissue lacks the flexible properties and cushion of normal cartilage.

The team theorized that there might be a way to influence skeletal stem cells to produce normal cartilage after microfracture. In a mouse model, the researchers used a molecule called BMP2 to initiate bone formation after microfracture. Next, they stopped the bone formation process midway with another molecule called VEGF. The result of this process was the generation of cartilage that had the same important properties as natural cartilage.

In a Stanford press release, Dr. Chan elaborated on these findings.

“What we ended up with was cartilage that is made of the same sort of cells as natural cartilage with comparable mechanical properties, unlike the fibrocartilage that we usually get. It also restored mobility to osteoarthritic mice and significantly reduced their pain.”

To show that this process could work in humans, the team then transferred human tissue into special mice that wouldn’t reject the tissue. They showed that human skeletal stem cells could be steered toward bone development but stopped at the cartilage stage.

The next stage for this research is to conduct experiments in larger animals before eventually starting human clinical trials. The ultimate goal of this treatment would be to help prevent arthritis by rejuvenating cartilage in the joints before it is badly degraded.

In the same press release, Dr. Longaker discusses the advantages of using BMP2 and VEGF for this process.

“BMP2 has already been approved for helping bone heal, and VEGF inhibitors are already used as anti-cancer therapies. This would help speed the approval of any therapy we develop.”

The full results of this study were published in Nature.

Stem Cell All-Stars, All For You

goldstein-larry

Dr. Larry Goldstein, UC San Diego

It’s not often you get a chance to hear some of the brightest minds around talk about their stem cell research and what it could mean for you, me and everyone else. That’s why we’re delighted to be bringing some of the sharpest tools in the stem cell shed together in one – virtual – place for our CIRM 2020 Grantee Meeting.

The event is Monday September 14th and Tuesday September 15th. It’s open to anyone who wants to attend and, of course, it’s all being held online so you can watch from the comfort of your own living room, or garden, or wherever you like. And, of course, it’s free.

BotaDaniela2261

Dr. Daniela Bota, UC Irvine

The list of speakers is a Who’s Who of researchers that CIRM has funded and who also happen to be among the leaders in the field. Not surprising as California is a global center for regenerative medicine. And you will of course be able to post questions for them to answer.

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Dr. Deepak Srivastava, Gladstone Institutes

The key speakers include:

Larry Goldstein: the founder and director of the UCSD Stem Cell Program talking about Alzheimer’s research

Irv Weissman: Stanford University talking about anti-cancer therapies

Daniela Bota: UC Irvine talking about COVID-19 research

Deepak Srivastava: Gladsone Institutes, talking about heart stem cells

Other topics include the latest stem cell approaches to COVID-19, spinal cord injury, blindness, Parkinson’s disease, immune disorders, spina bifida and other pediatric disorders.

You can choose one topic or come both days for all the sessions. To see the agenda for each day click here. Just one side note, this is still a work in progress so some of the sessions have not been finalized yet.

And when you are ready to register go to our Eventbrite page. It’s simple, it’s fast and it will guarantee you’ll be able to be part of this event.

We look forward to seeing you there.

Perseverance: from theory to therapy. Our story over the last year – and a half

Some of the stars of our Annual Report

It’s been a long time coming. Eighteen months to be precise. Which is a peculiarly long time for an Annual Report. The world is certainly a very different place today than when we started, and yet our core mission hasn’t changed at all, except to spring into action to make our own contribution to fighting the coronavirus.

This latest CIRM Annual Reportcovers 2019 through June 30, 2020. Why? Well, as you probably know we are running out of money and could be funding our last new awards by the end of this year. So, we wanted to produce as complete a picture of our achievements as we could – keeping in mind that we might not be around to produce a report next year.

Dr. Catriona Jamieson, UC San Diego physician and researcher

It’s a pretty jam-packed report. It covers everything from the 14 new clinical trials we have funded this year, including three specifically focused on COVID-19. It looks at the extraordinary researchers that we fund and the progress they have made, and the billions of additional dollars our funding has helped leverage for California. But at the heart of it, and at the heart of everything we do, are the patients. They’re the reason we are here. They are the reason we do what we do.

Byron Jenkins, former Naval fighter pilot who battled back from his own fight with multiple myeloma

There are stories of people like Byron Jenkins who almost died from multiple myeloma but is now back leading a full, active life with his family thanks to a CIRM-funded therapy with Poseida. There is Jordan Janz, a young man who once depended on taking 56 pills a day to keep his rare disease, cystinosis, under control but is now hoping a stem cell therapy developed by Dr. Stephanie Cherqui and her team at UC San Diego will make that something of the past.

Jordan Janz and Dr. Stephanie Cherqui

These individuals are remarkable on so many levels, not the least because they were willing to be among the first people ever to try these therapies. They are pioneers in every sense of the word.

Sneha Santosh, former CIRM Bridges student and now a researcher with Novo Nordisk

There is a lot of information in the report, charting the work we have done over the last 18 months. But it’s also a celebration of everyone who made it possible, and our way of saying thank you to the people of California who gave us this incredible honor and opportunity to do this work.

We hope you enjoy it.

CIRM Board Approves Third Clinical Trial for COVID-19

Dr. Xiaokui Zhang (left), Dr. Albert Wong (center), and Dr. Preet Chaudhary (right)

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $750,000 to Dr. Xiaokui Zhang at Celularity to conduct a clinical trial for the treatment of COVID-19.  This brings the total number of CIRM clinical trials to 64, including three targeting the coronavirus.

This trial will use blood stem cells obtained from the placenta to generate natural killer (NK) cells, a type of white blood cell that is a vital part of the immune system, and administer them to patients with COVID-19.  NK cells play an important role in defense against cancer and in fighting off viral infections.  The goal is to administer these cells to locate the active sites of COVID-19 infection and destroy the virus-infected cells.  These NK cells have been used in two other clinical trials for acute myeloid leukemia and multiple myeloma.

The Board also approved two additional awards for Discovery Stage Research (DISC2), which promote promising new technologies that could be translated to enable broad use and improve patient care.

One award for $100,000 was given to Dr. Albert Wong at Stanford.  Dr. Wong has recently received an award from CIRM to develop a vaccine that produces a CD8+ T cell response to boost the body’s immune response to remove COVID-19 infected cells.  The current award will enable him to expand on the initial approach to increase its potential to impact the Latinx and African American populations, two ethnicities that are disproportionately impacted by the virus in California.

The other award was for $249,996 and was given to Dr. Preet Chaudhary at the University of Southern California.  Dr. Chaudary will use induced pluripotent stem cells (iPSCs) to generate natural killer cells (NK). These NK cells will express a chimeric antigen receptor (CAR), a synthetic receptor that will directly target the immune cells to kill cells infected with the virus.  The ultimate goal is for these iPSC-NK-CAR cells to be used as a treatment for COVID-19. 

“These programs address the role of the body’s immune T and NK cells in combatting viral infection and CIRM is fortunate enough to be able to assist these investigators in applying experience and knowledge gained elsewhere to find targeted treatments for COVID-19” says Dr. Maria T. Millan, the President & CEO of CIRM. “This type of critical thinking reflects the resourcefulness of researchers when evaluating their scientific tool kits.  Projects like these align with CIRM’s track record of supporting research at different stages and for different diseases than the original target.”

The CIRM Board voted to endorse a new initiative to refund the agency and provide it with $5.5 billion to continue its work. The ‘California Stem Cell Research, Treatments and Cures Initiative of 2020 will appear on the November ballot. 

The Board also approved a resolution honoring Ken Burtis, PhD., for his long service on the Board. Dr. Burtis was honored for his almost four decades of service at UC Davis as a student, professor and administrator and for his 11 years on the CIRM Board as both a member and alternate member. In the resolution marking his retirement the Board praised him, saying “his experience, commitment, knowledge, and leadership, contributed greatly to the momentum of discovery and the future therapies which will be the ultimate outcome of the dedicated work of the researchers receiving CIRM funding.”

Jonathan Thomas, the Chair of the Board, said “Ken has been invaluable and I’ve always found him to have tremendous insight. He has served as a great source of advice and inspiration to me and to the ICOC in dealing with all the topics we have had to face.” 

Lauren Miller Rogen thanked Dr. Burtis, saying “I sat next to you at my first meeting and was feeling so extraordinarily overwhelmed and you went out of your way to explain all these big science words to me. You were always a source of help and support, and you explained things to me in a way that I always appreciated with my normal brain.”

Dr. Burtis said it has been a real honor and privilege to be on the Board. “I’ve been amazed and astounded at the passion and dedication that the Board and CIRM staff have brought to this work. Every meeting over the years there has been a moment of drama and then resolution and this Board always manages to reach agreement and serve the people of California.”

Stem Cell Agency Board Approves Three More Projects Targeting COVID-19

Dr. Jianhua Yu (left), Dr. Helen Blau (center), and Dr. Albert Wong (right)

The COVID-19 virus targets many different parts of the body, often with deadly or life-threatening consequences. This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investments in three early-stage research programs taking different approaches to battling the virus.

Dr. Jianhua Yu at the Beckman Research Institute of City of Hope was awarded $150,000 to use stem cells from umbilical cord blood to attack the virus. Dr. Yu and his team have many years of experience in taking cord blood cells and turning them into what are called chimeric antigen receptor (CAR) natural killer (NK) cells. The goal is to deploy these CAR NK cells to specifically target cells infected with COVID-19. This leverages the body of work at the City of Hope to develop this technology for cancer.

Dr. Helen Blau of Stanford University was awarded $149,996 to target recovery of muscle stem cells of the diaphragm in COVID-19 patients who have an extended period on a ventilator.

Patients with severe coronavirus often suffer respiratory failure and end up on mechanical ventilation that takes over the work of breathing. Over time, the diaphragm, the main muscle responsible for inhaling and exhaling, weakens and atrophies. There is no treatment for this kind of localized muscle wasting and it is anticipated that some of these patients will take months, if not years, to fully recover. Dr. Blau’s team proposes to develop a therapy with Prostaglandin E2 and Bupivacaine based on data generated by Dr. Blau’s group that these drugs, already approved by the FDA for other indications, have the potential to stimulate muscle stem cell recovery.

Dr. Albert Wong, also from Stanford University, was awarded $149,999 to develop vaccine candidates against COVID-19.

Most vaccine candidates are focused on getting the body to produce an antibody response to block the virus. However, Dr. Wong thinks that to be truly effective, a vaccine also needs to produce a CD8+ T cell response to augment an effective immune response to remove the COVID-19 infected cells that are hijacked by the virus to spread and cause illness.  This team will use the experience it gained using CIRM funds to vaccine against glioblastoma, a deadly brain cancer, to advance a similar approach to produce an effective cellular immune response to combat COVID-19.  

“CIRM is committed to supporting novel, multi-pronged approaches to battle this COVID-19 crisis that leverage solid science and knowledge gained in other areas.” says Dr. Maria T. Millan, the President & CEO of CIRM. “These three projects highlight three very different approaches to combatting the acute devastating health manifestations of COVID-19 as well as the debilitating sequelae that impact the ability to recover from the acute illness. Through this COVID funding opportunity, CIRM is enabling researchers to re-direct work they have already done, often with CIRM support, to quickly develop new approaches to COVID-19.”

Study shows that exercise rejuvenates muscle stem cells of old mice

Dr. Thomas Rando, Stanford University

While we’re all at home and practicing social distancing during this global pandemic, it has become a challenge to get in daily exercise. Aside from outward physical appearance, what other benefits does exercise hold? Dr. Thomas Rando and his team at Stanford University explored this question in more detail in a CIRM supported animal study.

The Stanford research team found that exercise played a key role in restoring the youthful properties in the muscle stem cells of old mice. Muscle stem cells play an important role in tissue regeneration. They are usually on standby alongside muscle fibers in a resting state known as quiescence until called upon to repair damage.

For this study, the researchers wanted to see if voluntary exercise had an effect on the muscle stem cells in mice. Older mice that were 20 months old, the equivalent of 60-70 human years, were given an exercise wheel where they were allowed to run at will. Younger mice that were 3-4 months old, the equivalent of 20-30 human years, were also given an exercise wheel and allowed to run at will. A separate group of younger and older mice were given a wheel that didn’t rotate to compare them with the groups of mice that exercised.

They found that the older animals that had exercised regularly were significantly better at repairing muscle damage compared to their counterparts that did not exercise. However, this exercise benefit was not observed between the younger group of mice.

The researchers also transplanted the muscle stem cells from the older mice that had exercised into younger mice that had not exercised. They found that the muscle stem cells from the older mice contributed more to the repair process than did those from the non-exercising mice.

What was also surprising is that injecting blood from an old mouse that had exercised into an old mouse that hadn’t created a similar benefit in the muscle stem cells. This finding suggests that exercise simulates the production of some factors that then circulate in the blood and enhance the function of older stem cells.

Lastly, the researchers were ably to identify a molecular pathway that activates the resting muscle stem cells in response to damage.

In a press release, Dr. Rando discusses how this discovery could potentially lead to the development of a drug that could rejuvenate muscle stem cells.

“If we could develop a drug that mimics this effect, we may be able to experience the benefit without having to do months of exercise.”

The full results of this study were published in Nature Metabolism.

Big time validation for early support

It’s not every day that a company and a concept that you helped support from the very beginning gets snapped up for $4.9 billion. But that’s what is happening with Forty Seven Inc. and their anti-cancer therapies. Gilead, another California company by the way, has announced it is buying Forty Seven Inc. for almost $5 billion.

The deal gives Gilead access to Forty Seven’s lead antibody therapy, magrolimab, which switches off CD47, a kind of “do not eat me” signal that cancer cells use to evade the immune system.

CIRM has supported this program from its very earliest stages, back in 2013, when it was a promising idea in need of funding. Last year we blogged about the progress it has made from a hopeful concept to an exciting therapy.

When Forty Seven Inc. went public in 2018, Dr. Irv Weissman, one of the founders of the company, attributed a lot of their success to CIRM’s support.

Dr. Irv Weissman

“The story of the funding of this work all of the way to its commercialization and the clinical trials reported in the New England Journal of Medicine is simply this: CIRM funding of a competitive grant took a mouse discovery of the CD47 ‘don’t eat me’ signal through all preclinical work to and through a phase 1 IND with the FDA. Our National Institutes of Health (NIH) did not fund any part of the clinical trial or preclinical run up to the trial, so it is fortunate for those patients and those that will follow, if the treatment continues its success in larger trials, that California voters took the state’s right action to fund research not funded by the federal government.”

Dr. Maria Millan, CIRM’s President & CEO, says the deal is a perfect example of CIRM’s value to the field of regenerative medicine and our ability to work with our grantees to make them as successful as possible.

“To say this is incredible would be an understatement! Words cannot describe how excited we are that this novel approach to battling currently untreatable malignancies has the prospect of making it to patients in need and this is a major step. Speaking on behalf of CIRM, we are very honored to have been a partner with Forty Seven Inc. from the very beginning.

CIRM Senior Science Officer, Dr. Ingrid Caras, was part of the team that helped a group of academic scientists take their work out of the lab and into the real world.

“I had the pleasure of working with and helping the Stanford team since CIRM provided the initial funding to translate the idea of developing CD47 blockade as a therapeutic approach. This was a team of superb scientists who we were fortunate to work closely with them to navigate the Regulatory environment and develop a therapeutic product. We were able to provide guidance as well as funding and assist in the ultimate success of this project.”

Forty Seven Inc. is far from the only example of this kind of support and collaboration. We have always seen ourselves as far more than just a funding agency. Money is important, absolutely. But so too is bringing the experience and expertise of our team to help academic scientists take a promising idea and turn it into a successful therapy.

After all that’s what our mission is, doing all we can to accelerate stem cell therapies to patients with unmet medical needs. And after a deal like this, Forty Seven Inc. is definitely accelerating its work.

Donor blood stem cells and T cells could help patients wean off immunosuppressive drugs after organ transplant

Dr. Samuel Strober is refining a process that eliminates the need for the many immunosuppresant drugs normally required after a transplant.
Image credit: Stanford Medicine News Center

In 2019, there were over 23,000 kidney transplants in the United States, according to figures from the United Network for Organ Sharing (UNOS). These transplants can be lifesaving, but the donated organ can be perceived as a foreign invader by the patient’s immune system and attacked. In order to protect the organ from attack, transplant recipients are required to take numerous drugs that suppress the immune system, which are referred to as immunosupressive (IS) drugs. Unfortunately, these drugs, while helping protect the organ, can also cause long term problems such as hypertension, diabetes, heart disease, infection, a high concentration of fats in the blood, and cancer.

To address this problem, Dr. Samuel Strober and his team at Stanford University are conducting a CIRM-funded clinical trial that gives patients getting a kidney transplant a mixture of their own blood cells and cells from the kidney donor, a process called mixed chimerism.

Pairing patients and donors for transplants is done via Human Leukocyte Antigen (HLA) matching. HLA are markers on most cells in your body and are used by your immune system to recognize which cells belong to the body. If you are fully HLA matched that means your cells and the donor cells are immunologically compatible, and so less likely to be rejected. If they are HLA haplotypes, it means they are close but not fully matched so rejection is more likely.

In the trial, fifty-one patients with end stage renal failure that had just received a kidney transplant were infused with blood stem cells (cells that can give rise to different kind of blood cells) and T cells (a cell that plays a role in the immune response) obtained from the donor to achieve a mixed chimerism. Of the 51 patients 29 were fully HLA matched, and 22 were HLA haplotype matched.

Standard IS drugs were administered to all the patients after transplantation and the patients were monitored from six to twelve months to ensure there was no organ rejection or graft vs host disease (GVHD), a condition where donated blood stem cells attack the body.

After this period, the patients were taken off the IS drugs and the results of this trial are very promising. Twenty-four of the fully HLA matched patients with a persistent mixed chimerism for at least six months were able to stop taking the IS drugs without evidence of rejection for at least two years. Ten HLA haplotype matched patients with a persistent mixed chimerism for at least twelve months were able to stop taking some of the IS drugs without rejection.

This is encouraging news for patients undergoing any kind of transplant, leading to hope that one day all patients might be able to get a life-saving organ without having to take the IS drugs forever.

The full results of this study were published in Science Translational Medicine.