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

Huge honor, hugely deserved for CIRM-funded stem cell researcher

Dr. Andy McMahon: Photo courtesy USC

Andy McMahon is one of the most understated, humble and low-key people you are ever likely to meet. He’s also one of the smartest. And he has a collection of titles to prove it. He is the W.M. Keck Provost and University Professor in USC’s departments of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine, and Biological Sciences at the Dornsife College of Letters, Arts and Sciences, a fellow of the American Association for the Advancement of Science, the American Academy of Arts and Sciences, the European Molecular Biology Organization, and the Royal Society.

Now you can add to that list that Andy is a member of the National Academy of Sciences (NAS). Election to the NAS is no ordinary honor. It’s one of the highest in the scientific world.

In a USC news release Dean Laura Mosqueda from the Keck School praised Andy saying: “We’re delighted that Dr. McMahon is being recognized as a newly elected member of the National Academy of Sciences. Because new members are elected by current members, this represents recognition of Dr. McMahon’s achievements by his most esteemed peers in all scientific fields.”

Not surprisingly CIRM has funded some of Andy’s work – well, we do pride ourselves on working with the best and brightest scientists – and that research is taking on added importance with the spread of COVID-19. Andy’s area of specialty is kidneys, trying to develop new ways to repair damaged or injured kidneys. Recent studies show that between 3 and 9 percent of patients with COVID-19 develop an acute kidney injury; in effect their kidneys suddenly stop working and many of these patients have to undergo dialysis to stay alive.

Even those who recover are at increased risk for developing more chronic, even end-stage kidney disease. That’s where Andy’s work could prove most useful. His team are using human stem cells to create mini artificial kidneys that have many of the same properties as the real thing. These so-called “organoids” enable us to study chronic kidney disease, come up with ideas to repair damage or slow down the progression of the disease, even help improve the chances of a successful transplant if that becomes necessary.

You can hear Andy talk about his work here:

CIRM is now funding a number of projects targeting COVID-19, including a clinical trial using convalescent plasma gel, and intends investing in more in the coming weeks and months. You can read about that here.

We are also funding several clinical trials targeting kidney failure. You can read about those on our Clinical Trials Dashboard page – diseases are listed alphabetically.

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.

The Most Important Gift of All

Photo courtesy American Hospital Association

There are many players who have a key role in helping make a stem cell therapy work. The scientists who develop the therapy, the medical team who deliver it and funders like CIRM who provide the money to make this all happen. But vital as they are, in some therapies there is another, even more important group; the people who donate life-saving organs and tissues for transplant and research.

Organ and tissue donation saves lives, increases knowledge of diseases, and allow for the development of novel medications to treat them. When individuals or their families authorize donation for transplant or medical research, they allow their loved ones to build a long-lasting legacy of hope that could not be accomplished in any other way.

Four of CIRM’s clinical trials involve organ donations – three kidney transplant programs (you can read about those here, here and here) and one targeting type 1 diabetes.

Dr. Nikole Neidlinger, the Chief Medical Officer with Donor Network West – the federally designated organ and tissue recovery organization for Northern California and Nevada – says it is important to recognize the critical contribution made in a time of grief and crisis by the families of deceased donors. 

“For many families who donate, a loved one has died, and they are in shock. Even so, they are willing to say yes to giving others a second chance at life and to help others to advance science. Without them, none of this would be possible. It’s the ultimate act of generosity and compassion.”

The latest CIRM-funded clinical trial involving donated tissue is with Dr. Peter Stock and his team at UCSF. They are working on a treatment for type 1 diabetes (T1D), where the body’s immune system destroys its own pancreatic beta cells. These cells are necessary to produce insulin, which regulates blood sugar levels in the body.

In the past people have tried transplanting beta cells, from donated pancreatic islets, into patients with type 1 diabetes to try and reverse the course of the disease. However, this requires islets from multiple donors and the shortage of organ and tissue donors makes this difficult to do.

Dr. Stock’s clinical trial at UCSF aims to address these limitations.  He is going to transplant both pancreatic islets and parathyroid glands, from the same donor, into T1 patients. It’s hoped this combination approach will increase beta cell survival, potentially boosting long-term insulin production and removing the need for multiple donors.  And because the transplant is placed in the patient’s forearm, it makes it easier to monitor the effectiveness and accessibility of the islet transplants. Of equal importance, the development of this site will facilitate the transplantation of stem cell derived beta cells, which are very close to clinical application.

“As a transplant surgeon, it is an absolute privilege to be able to witness the life-saving organ transplants made possible by the selfless generosity of the donor families. It is hard to imagine how families have the will to think about helping others at a time of their greatest grief. It is this willingness to help others that restores my faith in humanity”

Donor Network West plays a vital role in this process. In 2018 alone, the organization recovered 702 donor samples for research. Thanks to the generosity of the donors/donor families, the donor network has been able to provide parathyroid and pancreas tissue essential to make this clinical trial a success”

“One organ donor can save the lives of up to eight people and a tissue donor can heal more than 75 others,” says Dr. Neidlinger. “For families, the knowledge that they are transforming someone’s life, and possibly preventing another family from experiencing this same loss, can serve as a silver lining during their time of sorrow. .”

Organs that can be donated

Kidney (x2), Heart, Lungs (x2), Liver, Pancreas, Intestine

Tissue that can be donated

Corneas, Heart valves, Skin, Bone, Tendons, Cartilage, Veins

Currently, there are over 113,000 people in the U.S. waiting for an organ transplant, of which 84 % are in need of kidneys.  Sadly, 22 people die every day waiting for an organ transplant that does not come in time. The prospect of an effective treatment for type 1 diabetes means hope for thousands of people living with the chronic condition.

Rare Disease Gets Big Boost from California’s Stem Cell Agency

UC Irvine’s Dr. Leslie Thompson and patient advocate Frances Saldana after the CIRM Board vote to approve funding for Huntington’s disease

If you were looking for a poster child for an unmet medical need Huntington’s disease (HD) would be high on the list. It’s a devastating disease that attacks the brain, steadily destroying the ability to control body movement and speech. It impairs thinking and often leads to dementia. It’s always fatal and there are no treatments that can stop or reverse the course of the disease. Today the Board of the California Institute for Regenerative Medicine (CIRM) voted to support a project that shows promise in changing that.

The Board voted to approve $6 million to enable Dr. Leslie Thompson and her team at the University of California, Irvine to do the late stage testing needed to apply to the US Food and Drug Administration for permission to start a clinical trial in people. The therapy involves transplanting stem cells that have been turned into neural stem cells which secrete a molecule called brain-derived neurotrophic factor (BDNF), which has been shown to promote the growth and improve the function of brain cells. The goal is to slow down the progression of this debilitating disease.

“Huntington’s disease affects around 30,000 people in the US and children born to parents with HD have a 50/50 chance of getting the disease themselves,” says Dr. Maria T. Millan, the President and CEO of CIRM. “We have supported Dr. Thompson’s work for a number of years, reflecting our commitment to helping the best science advance, and are hopeful today’s vote will take it a crucial step closer to a clinical trial.”

Another project supported by CIRM at an earlier stage of research was also given funding for a clinical trial.

The Board approved almost $12 million to support a clinical trial to help people undergoing a kidney transplant. Right now, there are around 100,000 people in the US waiting to get a kidney transplant. Even those fortunate enough to get one face a lifetime on immunosuppressive drugs to stop the body rejecting the new organ, drugs that increase the risk for infection, heart disease and diabetes.  

Dr. Everett Meyer, and his team at Stanford University, will use a combination of healthy donor stem cells and the patient’s own regulatory T cells (Tregs), to train the patient’s immune system to accept the transplanted kidney and eliminate the need for immunosuppressive drugs.

The initial group targeted in this clinical trial are people with what are called HLA-mismatched kidneys. This is where the donor and recipient do not share the same human leukocyte antigens (HLAs), proteins located on the surface of immune cells and other cells in the body. Around 50 percent of patients with HLA-mismatched transplants experience rejection of the organ.

In his application Dr. Meyer said they have a simple goal: “The goal is “one kidney for life” off drugs with safety for all patients. The overall health status of patients off immunosuppressive drugs will improve due to reduction in side effects associated with these drugs, and due to reduced graft loss afforded by tolerance induction that will prevent chronic rejection.”

CIRM Invests in Medeor Therapeutics’ Phase 3 Clinical Trial to Help Kidney Transplant Patients

Steven Deitcher, President and CEO of Medeor Therapeutics, receives $18.8 million clinical award from CIRM to fund Phase 3 trial to help kidney transplant patients. (Photo: Todd Dubnicoff/CIRM)

Last week, CIRM’s governing Board approved funding for a Phase 3 clinical trial testing a stem cell-based treatment that could eliminate the need for immunosuppressive drugs in some patients receiving kidney transplants.

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 also increase a patient’s risk of infection, heart disease, cancer and diabetes.  Despite these drugs, many patients still lose transplanted organs due to rejection.

Reducing or eliminating the need for immunosuppressive drugs in kidney transplant patients is an unmet medical need that our Agency is well aware of. That’s why on Friday at our January ICOC meeting, the CIRM Board voted to invest $18.8 million dollars in a Phase III clinical trial sponsored by Medeor Therapeutics that will address this need head on.

Medeor, a biotechnology company located in San Mateo, California, is developing a stem cell-based therapy, called MDR-101, that they hope 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.

CIRM President and CEO, Dr. Maria Millan, commented in a CIRM news release:

Maria Millan

“These immunosuppressive drugs not only can cause harmful side effects, but they are also expensive and some patients lose their transplant either because they can’t afford to pay for the drugs, or because their effectiveness is not adequate. Medeor’s stem cell-based therapy aims to prevent transplant rejection and eliminate the need for immunosuppression in these kidney transplant patients. If they are successful, this approach could be developed for other organs including heart, liver, and lung transplants.”

CIRM funding will enable Medeor to test their stem cell-based treatment in a Phase 3 clinical trial. If the trial meets its objective in allowing patients to eliminate immunosuppressive drug use without rejection, Medeor may apply to the US Food and Drug Administration (FDA) for permission to market their therapy to patients in the United States.

Dr. Steven Deitcher, co-founder, President and CEO of Medeor, touched on the impact that this CIRM award will have on the advancement of their trial:

“We are very grateful for the financial support and validation from CIRM for the MDR-101 program. CIRM funding accelerates our timelines, and these timelines are what stand between needy patients and potential transformative therapies. This CIRM award combined with investor support represent a public-private collaboration that we hope will make a difference in the lives of organ transplant recipients in California, the entire U.S., and beyond.”

This is the fourth clinical trial targeting kidney disease that CIRM’s Board has funded. CIRM is also funding a Phase I trial testing a different stem cell-based therapy for end-stage kidney disease patients out of Stanford University led by Dr. Samuel Strober.

To learn more about the research CIRM is funding targeting kidney disease, check out our kidney disease fact sheet on our website.

California’s stem cell agency rounds up the year with two more big hits

icoc_dec2016-17

CIRM Board meeting with  Jake Javier, CIRM Chair Jonathan Thomas, Vice Chair Sen. Art Torres (Ret.) and President/CEO Randy Mills

It’s traditional to end the year with a look back at what you hoped to accomplish and an assessment of what you did. By that standard 2016 has been a pretty good year for us at CIRM.

Yesterday our governing Board approved funding for two new clinical trials, one to help kidney transplant patients, the second to help people battling a disease that destroys vision. By itself that is a no small achievement. Anytime you can support potentially transformative research you are helping advance the field. But getting these two clinical trials over the start line means that CIRM has also met one of its big goals for the year; funding ten new clinical trials.

If you had asked us back in the summer, when we had funded only two clinical trials in 2016, we would have said that the chances of us reaching ten trials by the end of the year were about as good as a real estate developer winning the White House. And yet……..

Helping kidney transplant recipients

The Board awarded $6.65 million to researchers at Stanford University who are using a deceptively simple approach to help people who get a kidney transplant. Currently people who get a transplant have to take anti-rejection medications for the rest of their life to prevent their body rejecting the new organ. These powerful immunosuppressive medications are essential but also come with a cost; they increase the risk of cancer, infection and heart disease.

icoc_dec2016-3

CIRM President/CEO Randy Mills addresses the CIRM Board

The Stanford team will see if it can help transplant patients bypass the need for those drugs by injecting blood stem cells and T cells (which play an important role in the immune system) from the kidney donor into the kidney recipient. The hope is by using cells from the donor, you can help the recipient’s body more readily adjust to the new organ and reduce the likelihood the body’s immune system will attack it.

This would be no small feat. Every year around 17,000 kidney transplants take place in the US, and many people who get a donor kidney experience fevers, infections and other side effects as a result of taking the anti-rejection medications. This clinical trial is a potentially transformative approach that could help protect the integrity of the transplanted organ, and improve the quality of life for the kidney recipient.

Fighting blindness

The second trial approved for funding is one we are already very familiar with; Dr. Henry Klassen and jCyte’s work in treating retinitis pigmentosa (RP). This is a devastating disease that typically strikes before age 30 and slowly destroys a person’s vision. We’ve blogged about it here and here.

Dr. Klassen, a researcher at UC Irvine, has developed a method of injecting what are called retinal progenitor cells into the back of the eye. The hope is that these cells will repair and replace the cells damaged by RP. In a CIRM-funded Phase 1 clinical trial the method proved safe with no serious side effects, and some of the patients also reported improvements in their vision. This raised hopes that a Phase 2 clinical trial using a larger number of cells in a larger number of patients could really see if this therapy is as promising as we hope. The Board approved almost $8.3 million to support that work.

Seeing is believing

How promising? Well, I recently talked to Rosie Barrero, who took part in the first phase clinical trial. She told me that she was surprised how quickly she started to notice improvements in her vision:

“There’s more definition, more colors. I am seeing colors I haven’t seen in years. We have different cups in our house but I couldn’t really make out the different colors. One morning I woke up and realized ‘Oh my gosh, one of them is purple and one blue’. I was by myself, in tears, and it felt amazing, unbelievable.”

Amazing was a phrase that came up a lot yesterday when we introduced four people to our Board. Each of the four had taken part in a stem cell clinical trial that changed their lives, even saved their lives. It was a very emotional scene as they got a chance to thank the group that made those trials, those treatments possible.

We’ll have more on that in a future blog.