Using heart stem cells to help boys battling a deadly disorder

 

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Caleb Sizemore, a young man with DMD, speaks to the CIRM Board about his treatment in the Capricor clinical trial.

It’s hard to imagine how missing just one tiny protein can have such a devastating impact on a person. But with Duchenne Muscular Dystrophy (DMD) the lack of a single protein called dystrophin has deadly consequences. Now a new study is offering hope we may be able to help people with this rare genetic disorder.

DMD is a muscle wasting condition that steadily destroys the muscles in the arms and legs, heart and respiratory system. It affects mostly boys and it starts early in life, sometimes as young as 3 years old, and never lets up. By early teens many boys are unable to walk and are in a wheelchair. Their heart and breathing are also affected. In the past most people with DMD didn’t survive their teens. Now it’s more common for them to live into their 20’s and 30’s, but not much beyond that.

Results from a clinical trial being run by Capricor Therapeutics – and funded by CIRM – suggest we may be able to halt, and even reverse, some of the impacts of DMD.

Capricor has developed a therapy called CAP-1002 using cells derived from heart stem cells, called cardiospheres. Boys and young men with DMD who were treated with CAP-1002 experienced what Capricor calls “significant and sustained improvements in cardiac structure and function, as well as skeletal muscle function.”

In a news release Dr. Ronald Victor, a researcher at Cedars-Sinai Heart Institute and the lead investigator for the trial, said they followed these patients for 12 months after treatment and the results are encouraging:

“Because Duchenne muscular dystrophy is a devastating, muscle-wasting disease that causes physical debilitation and eventually heart failure, the improvements in heart and skeletal muscle in those treated with a single dose of CAP-1002 are very promising and show that a subsequent trial is warranted. These early results provide hope for the Duchenne community, which is in urgent need of a major therapeutic breakthrough.”

According to the 12-month results:

  • 89 percent of patients treated with CAP-1002 showed sustained or improved muscle function compared to untreated patients
  • The CAP-1002 group had improved heart muscle function compared to the untreated group
  • The CAP-1002 group had reduced scarring on their heart compared to the untreated group.

Now, these results are still very early stage and there’s a danger in reading too much into them. However, the fact that they are sustained over one year is a promising sign. Also, none of the treated patients experienced any serious side effects from the therapy.

The team at Capricor now plans to go back to the US Food and Drug Administration (FDA) to get clearance to launch an even larger study in 2018.

For a condition like DMD, that has no cure and where treatments can simply slow down the progression of the disorder, this is a hopeful start.

Caleb Sizemore is one of the people treated in this trial. You can read his story and listen to him describing the impact of the treatment on his life.

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The life of a sleeping muscle stem cell is very busy

For biological processes, knowing when to slow down is as important as knowing when to step on the accelerator. Take for example muscle stem cells. In a healthy state, these cells mostly lay quiet and rarely divide but upon injury, they bolt into action by dividing and specializing into new muscle cells to help repair damaged muscle tissue. Once that mission is accomplished, the small pool of muscle stem cells is replenished through self-renewal before going back into a dormant, or quiescent, state.

muscle stem cell

Muscle stem cell (pink with green outline) sits along a muscle fiber. Image: Michael Rudnicki/OIRM

“Dormant” may not be the best way to describe it because a lot of activity is going on within the cells to maintain its sleepy state. And a better understanding of the processes at play in a dormant state could reveal insights about treating aging or diseased muscles which often suffer from a depletion of muscle stem cells. One way to analyze cellular activity is by examining RNA transcripts which are created when a gene is turned “on”. These transcripts are the messenger molecules that provide a gene’s instructions for making a particular protein.

By observing something, you change it
In order to carry out the RNA transcript analyses in animal studies, researchers must isolate and purify the stem cells from muscle tissue. The worry here is that all of the necessary poking of prodding of the cells during the isolation method will alter the RNA transcripts leading to a misinterpretation of what is actually happening in the native muscle tissue. To overcome this challenge, Dr. Thomas Rando and his team at Stanford University applied a recently developed technique that allowed them to tag and track the RNA transcripts within living mice.

The CIRM-funded study reported today in Cell Reports found that there are indeed significant differences in results when comparing the standard in vitro lab method to the newer in vivo method. As science writer Krista Conger summarized in a Stanford Medical School press release, those differences led to some unexpected results that hadn’t been observed previously:

“The researchers were particularly surprised to learn that many of the RNAs made by the muscle stem cells in vivo are either degraded before they are made into proteins, or they are made into proteins that are then rapidly destroyed — a seemingly shocking waste of energy for cells that spend most of their lives just cooling their heels along the muscle fiber.”

It takes a lot of energy to stay ready
Dr. Rando thinks that these curious observations do not point to an inefficient use of a cell’s resources but instead, “it’s possible that this is one way the cells stay ready to undergo a rapid transformation, either by blocking degradation of RNA or proteins or by swiftly initiating translation of already existing RNA transcripts.”

The new method provides Rando’s team a whole new perceptive on understanding what’s happening behind the scenes during a muscle stem cell’s “dormant” state. And Rando thinks the technique has applications well beyond this study:

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Thomas Rando

“It’s so important to know what we are and are not modeling about the state of these cells in vivo. This study will have a big impact on how researchers in the field think about understanding the characteristics of stem cells as they exist in their native state in the tissue.”

 

 

Using stem cells to take an inside approach to fixing damaged livers

Often on the Stem Cellar we write about work that is in a clinical trial. But getting research to that stage takes years and years of dedicated work. Over the next few months we are going to profile some of the scientists we fund who are doing Discovery, or early stage research, to highlight the importance of this work in developing the treatments that could ultimately save lives.

 This first profile is by Pat Olson, Ph.D., CIRM’s Vice President of Discovery & Translation

liver

Most of us take our liver for granted.  We don’t think about the fact that our liver carries out more than 500 functions in our bodies such as modifying and removing toxins, contributing to digestion and energy production, and making substances that help our blood to clot.  Without a liver we probably wouldn’t live more than a few days.

Our liver typically functions well but certain toxins, viral infections, long-term excess alcohol consumption and metabolic diseases such as obesity and type 2 diabetes can have devastating effects on it.  Under these conditions, functional liver cells, called hepatocytes, die and are replaced with cells called myofibroblasts.  Myofibroblasts are cells that secrete excess collagen leading to fibrosis, a form of scarring, throughout the liver.  Eventually, a liver transplant is required but the number of donor livers available for transplant is small and the number of persons needing a functional liver is large.  Every year in the United States,  around 6,000 patients receive a new liver and more than 35,000 patients die of liver disease.

Searching for options

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Dr. Holger Willenbring

Dr. Holger Willenbring, a physician scientist at UCSF, is one of the CIRM-funded researchers pursuing a stem cell/regenerative medicine approach to discover a treatment for patients with severe liver disease.  There are significant challenges to treating liver disease including getting fully multi-functional hepatocytes and getting them to engraft and/or grow sufficiently to achieve adequate mass for necessary liver functions.

In previous CIRM–funded discovery research, Dr. Willenbring and his team showed that they could partially reprogram human fibroblasts (the most common cell found in connective tissue) and then turn them into immature hepatocytes.  (see our Spotlight on Liver Disease video from 2012 featuring Dr. Willenbring.) These immature hepatocytes, when transplanted into an immune-deficient mouse model of human liver failure, were shown to mature over time into hepatocytes that were comparable to normal human hepatocytes both in their gene expression and their function.

This was an important finding in that it suggested that the liver environment in a living animal (in vivo), rather than in a test tube (in vitro) in the laboratory, is important for full multi-functional maturation of hepatocytes.  The study also showed that these transplanted immature human hepatocytes could proliferate and improve the survival of this mouse model of chronic human liver disease.  But, even though this model was designed to emphasizes the growth of functional human hepatocytes, the number of cells generated was not great enough to suggest that transplantation could be avoided

A new approach

Dr. Willenbring and his team are now taking the novel approach of direct reprogramming inside the mouse.  With this approach, he seeks to avoid the challenge of low engraftment and proliferation of transplanted hepatocytes generated in the lab and transplanted. Instead, they aim to take advantage of the large number of myofibroblasts in the patient’s scarred liver by turning them directly into hepatocytes.

Recently, he and his team have shown proof-of principle that they can deliver genes to myofibroblasts and turn them into hepatocytes in a mouse. In addition these in vivo myofibroblasts-derived hepatocytes are multi-functional, and can multiply in number, and can even reverse fibrosis in a mouse with liver fibrosis.

From mice to men (women too)

Our latest round of funding for Dr. Willenbring has the goal of moving and extending these studies into human cells by improving the specificity and effectiveness of reprogramming of human myofibroblasts into hepatocytes inside the animal, rather than the lab.

He and his team will then conduct studies to test the therapeutic effectiveness and initial safety of this approach in preclinical models. The ultimate goal is to generate a potential therapy that could eventually provide hope for the 35,000 patients who die of liver disease each year in the US.

 

 

Surprise findings about bone marrow transplants could lead to more effective stem cell therapies

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Bone marrow transplant: Photo courtesy FierceBiotech

Some medical therapies have been around for so long that we naturally assume we understand how they work. That’s not always the case. Take aspirin for example. It’s been used for more than 4,000 years to treat pain and inflammation but it was only in the 1970’s that we really learned how it works.

The same is now true for bone marrow transplants. Thanks to some skilled research at the Fred Hutchinson Cancer Research Center in Seattle.

Bone marrow transplants have been used for decades to help treat deadly blood cancers such as leukemia and lymphoma. The first successful bone marrow transplant was in the late 1950’s, involving identical twins, one of whom had leukemia. Because the twins shared the same genetic make-up the transplant avoided potentially fatal problems like graft-vs-host-disease, where the transplanted cells attack the person getting them. It wasn’t until the 1970’s that doctors were able to perform transplants involving people who were not related or who did not share the same genetic make-up.

In a bone marrow or blood stem cell transplant, doctors use radiation or chemotherapy to destroy the bone marrow in a patient with, say, leukemia. Then cancer-free donor blood stem cells are transplanted into the patient to help create a new blood system, and rebuild their immune system.

Surprise findings

In the study, published in the journal Science Translational Medicine, the researchers were able to isolate a specific kind of stem cell that helps repair and rebuild the blood and immune system.

The team found that a small subset of blood stem cells, characterized by having one of three different kinds of protein on their surface – CD34 positive, CD45RA negative and CD90 positive – did all the work.

In a news release Dr. Hans-Peter Kiem, a senior author on the study, says some of their initial assumptions about how bone marrow transplants work were wrong:

“These findings came as a surprise; we had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system. This population does it all.”

Tracking the cells

The team performed bone-marrow transplants on monkeys and then followed those animals over the next seven years, observing what happened as the donor cells grew and multiplied.

They tracked hundreds of thousands of cells in the blood and found that, even though the cells with those three proteins on the surface made up just five percent of the total blood supply, they were responsible for rebuilding the entire blood and immune system.

Study co-author Dr. Jennifer Adair said they saw evidence of this rebuilding within 10 days of the transplant:

“Our ability to track individual blood cells that developed after transplant was critical to demonstrating that these really are stem cells.”

Hope for the future

It’s an important finding because it could help researchers develop new ways of delivering bone marrow transplants that are both safer and more effective. Every year some 3,000 people die because they cannot find a matching donor. Knowing which stem cells are specifically responsible for an effective transplant could help researchers come up with ways to get around that problem.

Although this work was done in monkeys, the scientists say humans have similar kinds of stem cells that appear to act in the same way. Proving that’s the case will obviously be the next step in this research.

 

Stem cell stories that caught our eye: the tale of a tail that grows back and Zika’s devious Trojan Horse

The tale of a tail that grows back (Kevin McCormack)

Ask people what they know about geckos and the odds are they’ll tell you geckos have English accents and sell car insurance. Which tells you a lot more about the power of advertising than it does about the level of knowledge about lizards. Which is a shame, because the gecko has some amazing qualities, not the least of which is its ability to re-grow its tail. Now some researchers have discovered how it regenerates its tail, and what they’ve learned could one day help people with spinal cord injuries.

Geckos often detach a bit of their tail when being pursued by a predator, then grow a new one over the course of 30 days. Researchers at the University of Guelph in Canada found that the lizards use a combination of stem cells and proteins to do that.

They found that geckos have stem cells in their tail called radial glias. Normally these cells are dormant but that changes when the lizard loses its tail. As Matthew Vickaryous, lead author of the study, said in a news release:

“But when the tail comes off everything temporarily changes. The cells make different proteins and begin proliferating more in response to the injury. Ultimately, they make a brand new spinal cord. Once the injury is healed and the spinal cord is restored, the cells return to a resting state.”

Vickaryous hopes that understanding how the gecko can repair what is essentially an injury to its spinal cord, we’ll be better able to develop ways to help people with the same kind of injury.

The study is published in the Journal of Comparative Neurology.

Zika virus uses Trojan Horse strategy to infect developing brain
In April 2015, the World Health Organization declared that infection by Zika virus and its connection to severe birth defects was an international public health emergency. The main concern has been the virus’ link to microcephaly, a condition in which abnormal brain development causes a smaller than normal head size at birth. Microcephaly leads to number of problems in these infants including developmental delays, seizures, hearing loss and difficulty swallowing.

A false color micrograph shows microglia cells (green) infected by the Zika virus (blue). Image Muotri lab/UCSD

Since that time, researchers have been racing to better understand how Zika infection affects brain development with the hope of finding treatment strategies. Now, a CIRM-funded study in Human Molecular Genetics reports important new insights about how Zika virus may be transmitted from infected pregnant women to their unborn babies.

The UCSD researchers behind the study chose to focus on microglia cells. In a press release, team leader Alysson Muotri explained their rationale for targeting these cells:

“During embryogenesis — the early stages of prenatal development — cells called microglia form in the yolk sac and then disperse throughout the central nervous system (CNS) of the developing child. Considering the timing of [Zika] transmission, we hypothesized that microglia might be serving as a Trojan horse to transport the virus during invasion of the CNS.”

In the developing brain, microglia continually travel throughout the brain and clear away dead or infected cells. Smuggling itself aboard microglia would give Zika a devious way to slip through the body’s defenses and infect other brain cells. And that’s exactly what Dr. Muotri’s team found.

Using human induced pluripotent stem cells (iPSCs), they generated brain stem cells – the kind found in the developing brain – and in lab dish infected them with Zika virus. When iPSC-derived microglia were added to the infected neural stem cells, the microglia gobbled them up and destroyed them, just as they would do in the brain. But when those microglia were placed next to uninfected brain stem cells, the Zika virus was easily transmitted to those cells. Muotri summed up the results this way:

“Our findings show that the Zika virus can infect these early microglia, sneaking into the brain where they transmit the virus to other brain cells, resulting in the devastating neurological damage we see in some newborns.”

The team went on to show that an FDA-approved drug to treat hepatitis – a liver disease often caused by viral infection – was effective at decreasing the infection of brain stem cells by Zika-carrying microglia. Since these studies were done in petri dishes, more research will be required to confirm that the microglia are a true drug target for stopping the devastating impact of Zika on newborns.

A Patient Advocate’s Personal Manifesto

Janni and Obama

President Obama and Janni Lehrer-Stein

Janni Lehrer-Stein was just 26 when she was diagnosed with a degenerative eye disease and told she was going to be blind within six months. The doctor who gave her the news told her “But don’t worry, people like you are usually hit and killed by a bus long before they go completely blind.”

At the time she was recently married, had just graduated law school and landed her dream job with the government in Washington DC, litigating workplace discrimination. The news about her eyesight stopped her in her tracks.

But not for long. If you ever met Janni you would know that nothing stops her for long.

I was fortunate enough to hear Janni talk at a Foundation Fighting Blindness event in the San Francisco Bay Area last weekend. I was part of a panel discussion on new approaches to treating vision loss, including the research that CIRM is funding.

Janni didn’t talk about stem cells, instead she focused on the importance of the patient advocate voice, community, and their determination. She said one of the most important things anyone battling a life-threatening or life-changing disease or disorder needs to remember is that it’s not about disability, it’s about capability. It’s about what you can do rather than what you cannot.

Janni laid out her “manifesto” for things she says will help you keep that thought uppermost in your mind.

1) Show up. It’s that simple and that important. You have to show up. You have to get educated, you have to learn all you can about your condition so you know what you can do and what you can’t do. You have to share that information with others. You have to be there for others. Don’t just show up for yourself. Show up for others who can’t be there.

2) Share this information. Janni talked about a website called My Retina Tracker which is helping drive research into the causes of retinal diseases like retinitis pigmentosa and macular degeneration, and hopefully will lead to treatments and even cures. She says the more people work together, the more we combine our resources, the more effective we can be.

3) Support the researchers. Janni says while raising awareness is important, raising money is just as important. Without money there can be no research, and without research no treatments or cures. Janni says it doesn’t matter how you do it – a charity walk, a Go Fund me campaign, petitioning your state or federal elected representatives to urge them to fund research – everything counts, every dollar helps.

4) Remember you are part of a wider community. Janni says no one ever won a battle on their own; it takes a lot of people to fight and win the right to be treated equally. And it takes a lot of effort to stop those rights from being rolled back.

Janni hasn’t let losing her sight hold her back. In 2011, she was appointed by President Obama, and confirmed by the U.S. Senate, to the National Council on Disability where she served two terms advising the President and Congress on national disability policy.

Now she has returned home to the San Francisco Bay Area, but she is no less determined to make a difference and no less determined to fight for the rights of patients and patient advocates.

In an article on Medium she shares her feelings about being a patient advocate:

“The America that I so deeply respect is one that embraces, values and respects the contributions of us all. My America includes every one of us, regardless of our gender, race, age or disability. Our America is a place where, regardless of whether we are sighted or blind, we have the same opportunities, for which we are equally considered. Our America includes every one of us who wishes to make the world a more peaceful, responsible, and inclusive environment that is tolerant of all differences and abilities, physical or otherwise. To me, those differences make our lives richer, give our contributions more meaning, and lead to a brighter future for the next generation.”

 

Stanford scientists are growing brain stem cells in bulk using 3D hydrogels

This blog is the final installment in our #MonthofCIRM series. Be sure to check out our other blogs highlighting important advances in CIRM-funded research and initiatives.

Neural stem cells from the brain have promising potential as cell-based therapies for treating neurological disorders such as Alzheimer’s disease, Parkinson’s, and spinal cord injury. A limiting factor preventing these brain stem cells from reaching the clinic is quantity. Scientists have a difficult time growing large populations of brain stem cells in an efficient, cost-effective manner while also maintaining the cells in a stem cell state (a condition referred to as “stemness”).

CIRM-funded scientists from Stanford University are working on a solution to this problem. Dr. Sarah Heilshorn, an associate professor of Materials Science and Engineering at Stanford, and her team are engineering 3D hydrogel technologies to make it easier and cheaper to expand high-quality neural stem cells (NSCs) for clinical applications. Their research was published yesterday in the journal Nature Materials.

Stem Cells in 3D

Similar to how moviegoers prefer to watch the latest Star Wars installment in 3D, compared to the regular screen, scientists are turning to 3D materials called hydrogels to grow large numbers of stem cells. Such an environment offers more space for the stem cells to proliferate and expand their numbers while keeping them happy in their stem cell state.

To find the ideal conditions to grow NSCs in 3D, Heilshorn’s team tested two important properties of hydrogels: stiffness and degradability (or how easy it is to remodel the structure of the hydrogel material). They designed a range of hydrogels, made from proteins with elastic qualities, that varied in these two properties. Interestingly, they found that the stiffness of the material did not have a profound effect on the “stemness” of NSCs. This result contrasts with other types of adult stem cells like muscle stem cells, which quickly differentiate into mature muscle cells when exposed to stiffer materials.

On the other hand, the researchers found that it was crucial for the NSCs to be able to remodel their 3D environment. NSCs maintained their stemness by secreting enzymes that broke down and rearranged the molecules in the hydrogels. If this enzymatic activity was blocked, or if the cells were grown in hydrogels that couldn’t be remodeled easily, NSCs lost their stemness and stopped proliferating. The team tested two other hydrogel materials and found the same results. As long as the NSCs were in a 3D environment they could remodel, they were able to maintain their stemness.

NSCs maintain their stemness in hydrogels that can be remodeled easily. Nestin (green) and Sox2 (red) are markers that indicate “high-quality” NSCs. (Image courtesy of Chris Madl, Stanford)

Caption: NSCs maintain their stemness in hydrogels that can be remodeled easily. Nestin (green) and Sox2 (red) are markers that indicate “high-quality” NSCs. (Images courtesy of Chris Madl)

Christopher Madl, a PhD student in the Heilshorn lab and the first author on the study, explained how remodeling their 3D environment allows NSCs to grow robustly in an interview with the Stem Cellar:

Chris Madl

“In this study, we identified that the ability of the neural stem cells to dynamically remodel the material was critical to maintaining the correct stem cell state. Being able to remodel (or rearrange) the material permitted the cells to contact each other.  This cell-cell contact is responsible for maintaining signals that allow the stem cells to stay in a stem-like state. Our findings allow expansion of neural stem cells from relatively low-density cultures (aiding scale-up) without the use of expensive chemicals that would otherwise be required to maintain the correct stem cell behavior (potentially decreasing cost).”

To 3D and Beyond

When asked what’s next on the research horizon, Heilshorn said two things:

Sarah Heilshorn

“First, we want to see if other stem cell types – for example, pluripotent stem cells – are also sensitive to the “remodel-ability” of materials. Second, we plan to use our discovery to create a low-cost, reproducible material for efficient expansion of stem cells for clinical applications. In particular, we’d like to explore the use of a single material platform that is injectable, so that the same material could be used to expand the stem cells and then transplant them.”

Heilshorn is planning to apply the latter idea to advance another study that her team is currently working on. The research, which is funded by a CIRM Tools and Technologies grant, aims to develop injectable hydrogels containing NSCs derived from human induced pluripotent stem cells to treat mice, and hopefully one day humans, with spinal cord injury. Heilshorn explained,

“In our CIRM-funded studies, we learned a lot about how neural stem cells interact with materials. This lead us to realize that there’s another critical bottleneck that occurs even before the stage of transplantation: being able to generate a large enough number of high-quality stem cells for transplantation. We are developing materials to improve the transplantation of stem cell-derived therapies to patients with spinal cord injuries. Unfortunately, during the transplantation process, a lot of cells can get damaged. We are now creating injectable materials that prevent this cell damage during transplantation and improve the survival and engraftment of NSCs.”

An injectable material that promotes the expansion of large populations of clinical grade stem cells that can also differentiate into mature cells is highly desired by scientists pursuing the development of cell replacement therapies. Heilshorn and her team at Stanford have made significant progress on this front and are hoping that in time, this technology will prove effective enough to reach the clinic.

CIRM stories that caught our eye: UCSD team stops neuromuscular disease in mice, ALS trial enrolls 1st patients and Q&A with CIRM Prez

Ordinarily, we end each week at the Stem Cellar with a few stem cell stories that caught our eye. But, for the past couple of weeks we’ve been busy churning out stories related to our Month of CIRM blog series, which we hope you’ve found enlightening. To round out the series, we present this “caught our eye” blog of CIRM-specific stories from the last half of October.

Stopping neurodegenerative disorder with blood stem cells. (Karen Ring)

CIRM-funded scientists at the UC San Diego School of Medicine may have found a way to treat a progressive neuromuscular disorder called Fredreich’s ataxia (FA). Their research was published last week in the journal Science Translational Medicine.

FA is a genetic disease that attacks the nervous tissue in the spinal cord leading to the loss of sensory nerve cells that control muscle movement. Early on, patients with FA experience muscle weakness and loss of coordination. As the disease progresses, FA can cause scoliosis (curved spine), heart disease and diabetes. 1 in 50,000 Americans are afflicted with FA, and there is currently no effective treatment or cure for this disease.

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In this reconstituted schematic, blood stem cells transplanted in a mouse model of Friedreich’s ataxia differentiate into microglial cells (red) and transfer mitochondrial protein (green) to neurons (blue), preventing neurodegeneration. Image courtesy of Stephanie Cherqui, UC San Diego School of Medicine.

UCSD scientists, led by CIRM grantee Dr. Stephanie Cherqui, found in a previous study that transplanting blood stem and progenitor cells was an effective treatment for preventing another genetic disease called cystinosis in mice. Cherqui’s cystinosis research is currently being funded by a CIRM late stage preclinical grant.

In this new study, the UCSD team was curious to find out whether a similar stem cell approach could also be an effective treatment for FA. The researchers used an FA transgenic mouse model that was engineered to harbor two different human mutations in a gene called FXN, which produces a mitochondrial protein called frataxin. Mutations in FXN result in reduced expression of frataxin, which eventually leads to the symptoms experienced by FA patients.

When they transplanted healthy blood stem and progenitor cells (HSPCs) from normal mice into FA mice, the cells developed into immune cells called microglia and macrophages. They found the microglia in the brain and spinal cord and the macrophages in the spinal cord, heart and muscle tissue of FA mice that received the transplant. These normal immune cells produced healthy frataxin protein, which was transferred to disease-affected nerve and muscle cells in FA mice.

Cherqui explained their study’s findings in a UC San Diego Health news release:

“Transplantation of wildtype mouse HSPCs essentially rescued FA-impacted cells. Frataxin expression was restored. Mitochondrial function in the brains of the transgenic mice normalized, as did in the heart. There was also decreased skeletal muscle atrophy.”

In the news release, Cherqui’s team acknowledged that the FA mouse model they used does not perfectly mimic disease progression in humans. In future studies, the team will test their method on other mouse models of FA to ultimately determine whether blood stem cell transplants will be an effective treatment option for FA patients.

Brainstorm’s CIRM funded clinical trial for ALS enrolls its first patients
“We have been conducting ALS clinical trials for more than two decades at California Pacific Medical Center (CPMC) and this is, by far, the most exciting trial in which we have been involved to date.”

Those encouraging words were spoken by Dr. Robert Miller, director of CPMC’s Forbes Norris ALS Research Center in an October 16th news release posted by Brainstorm Cell Therapeutics. The company announced in the release that they had enrolled the first patients in their CIRM-funded, stem cell-based clinical trial for the treatment of amyotrophic lateral sclerosis (ALS).

BrainStorm

Also known as Lou Gehrig’s disease, ALS is a cruel, devastating disease that gradually destroys motor neurons, the cells in the brain or spinal cord that instruct muscles to move. People with the disease lose the ability to move their muscles and, over time, the muscles atrophy leading to paralysis. Most people with ALS die within 3 to 5 years from the onset of symptoms and there is no effective therapy for the disease.

Brainstorm’s therapy product, called NurOwn®, is made from mesenchymal stem cells that are taken from the patient’s own bone marrow. These stem cells are then modified to boost their production and release of factors, which are known to help support and protect the motor neurons destroyed by the disease. Because the cells are derived directly from the patient, no immunosuppressive drugs are necessary, which avoids potentially dangerous side effects. The trial aims to enroll 200 patients and is a follow up of a very promising phase 2 trial. CIRM’s $16 million grant to the Israeli company which also has headquarters in the United States will support clinical studies at multiple centers in California. And Abla Creasey, CIRM’s Senior Director of Strategic Infrastructure points out in the press release, the Agency support of this trial goes beyond this single grant:

“Brainstorm will conduct this trial at multiple sites in California, including our Alpha Clinics Network and will also manufacture its product in California using CIRM-funded infrastructure.”

An initial analysis of the effectiveness of NurOwn® in this phase 3 trial is expected in 2019.

CIRM President Maria Millan reflects on her career, CIRM’s successes and the outlook for stem cell biology 

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Maria T. Millan, M.D., CIRM President and CEO

RegMedNet a networking website that provides content related to the regenerative medicine community, published an interview this morning with Maria Millan, M.D., CIRM’s new President and CEO. The interview covers the impressive accomplishments that Dr. Millan had achieved before coming to CIRM, with details that even some of us CIRM team members may not have been aware of. In addition to describing her pre-CIRM career, Dr. Millan also describes the Agency’s successes during her term as Vice President of CIRM’s Therapeutics group and she gives her take on future of Agency and the stem cell biology field in general over the next five years and beyond. File this article under “must read”.

CIRM Board invests in three new stem cell clinical trials targeting arthritis, cancer and deadly infections

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Arthritis of the knee

Every day at CIRM we get calls from people looking for a stem cell therapy to help them fight a life-threatening or life-altering disease or condition. One of the most common calls is about osteoarthritis, a painful condition where the cartilage that helps cushion our joints is worn away, leaving bone to rub on bone. People call asking if we have something, anything, that might be able to help them. Now we do.

At yesterday’s CIRM Board meeting the Independent Citizens’ Oversight Committee or ICOC (the formal title of the Board) awarded almost $8.5 million to the California Institute for Biomedical Research (CALIBR) to test a drug that appears to help the body regenerate cartilage. In preclinical tests the drug, KA34, stimulated mesenchymal stem cells to turn into chondrocytes, the kind of cell found in healthy cartilage. It’s hoped these new cells will replace those killed off by osteoarthritis and repair the damage.

This is a Phase 1 clinical trial where the goal is primarily to make sure this approach is safe in patients. If the treatment also shows hints it’s working – and of course we hope it will – that’s a bonus which will need to be confirmed in later stage, and larger, clinical trials.

From a purely selfish perspective, it will be nice for us to be able to tell callers that we do have a clinical trial underway and are hopeful it could lead to an effective treatment. Right now the only alternatives for many patients are powerful opioids and pain killers, surgery, or turning to clinics that offer unproven stem cell therapies.

Targeting immune system cancer

The CIRM Board also awarded Poseida Therapeutics $19.8 million to target multiple myeloma, using the patient’s own genetically re-engineered stem cells. Multiple myeloma is caused when plasma cells, which are a type of white blood cell found in the bone marrow and are a key part of our immune system, turn cancerous and grow out of control.

As Dr. Maria Millan, CIRM’s President & CEO, said in a news release:

“Multiple myeloma disproportionately affects people over the age of 65 and African Americans, and it leads to progressive bone destruction, severe anemia, infectious complications and kidney and heart damage from abnormal proteins produced by the malignant plasma cells.  Less than half of patients with multiple myeloma live beyond 5 years. Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”

In a news release from Poseida, CEO Dr. Eric Ostertag, said the therapy – called P-BCMA-101 – holds a lot of promise:

“P-BCMA-101 is elegantly designed with several key characteristics, including an exceptionally high concentration of stem cell memory T cells which has the potential to significantly improve durability of response to treatment.”

Deadly infections

The third clinical trial funded by the Board yesterday also uses T cells. Researchers at Children’s Hospital of Los Angeles were awarded $4.8 million for a Phase 1 clinical trial targeting potentially deadly infections in people who have a weakened immune system.

Viruses such as cytomegalovirus, Epstein-Barr, and adenovirus are commonly found in all of us, but our bodies are usually able to easily fight them off. However, patients with weakened immune systems resulting from chemotherapy, bone marrow or cord blood transplant often lack that ability to combat these viruses and it can prove fatal.

The researchers are taking T cells from healthy donors that have been genetically matched to the patient’s immune system and engineered to fight these viruses. The cells are then transplanted into the patient and will hopefully help boost their immune system’s ability to fight the virus and provide long-term protection.

Whenever you can tell someone who calls you, desperately looking for help, that you have something that might be able to help them, you can hear the relief on the other end of the line. Of course, we explain that these are only early-stage clinical trials and that we don’t know if they’ll work. But for someone who up until that point felt they had no options and, often, no hope, it’s welcome and encouraging news that progress is being made.

 

 

CIRM’s Clinical Dashboard: An Interactive Guide Makes Learning About Stem Cell Trials Easier

This blog is part of the Month of CIRM series on the Stem Cellar.

The questions we get most frequently from members of the public are about our clinical trials. Typically, people want to know what stem cell-based trials our Agency is funding or whether we’re funding trials for specific diseases or disorders that either they or their loved one are afflicted with.

During these conversations, we refer people to our website’s clinical trials page, which lists all of the trials CIRM has funded since our Agency was established in 2004. This page previously featured a simple table (see image below) that listed basic information about CIRM-funded trials including links to CIRM grants and to trial details on clinicaltrials.gov. This table was not the most exciting way to feature our clinical portfolio, but it did what it needed to do at the time.

CIRM’s former clinical trials table.

Here’s where I reference Bob Dylan’s famous lyric, “the times, they are a-changing”. CIRM’s clinical portfolio has rapidly expanded from 17 funded trials to 40 since the launch of our Strategic Plan in 2016. That’s 23 new trials in less than two years. The number of CIRM-funded trials will continue to climb steadily each year as we strive to reach our Strategic Plan’s goal of funding an additional 27 new trials by 2020.

This rapid expansion in our clinical portfolio is very exciting because it brings us closer to achieving our mission of accelerating stem cell treatments to patients with unmet medical needs. It also means that it’s finally time to retire our old clinical trials table and replace it with something that does our expanding portfolio justice, and makes it easier for anyone who is interested to learn about the trials we’re funding.

That something is already here and it’s called the Clinical Dashboard. It’s an interactive Dashboard that allows users to filter through CIRM’s clinical portfolio by clicking on tabs for major disease indications. Users can also sort trials by disease area, investigator, organization, and the phase or status of the trial.

The CIRM Clinical Dashboard was launched in September, 2017.

The Dashboard is a snapshot of the essential information a scientist, patient, or member of the public needs to know about our trials. Users who want to learn more about a given trial, beyond what’s listed in the Dashboard, can click on the arrow in the “Detail” column. This takes users to a detailed trials page featuring information about the treatment being tested, the CIRM clinical award that funded the trial, information about trial’s design, goals and patient enrollment status, and any recently published news about the trial.

The details page also has resources specifically for patients including a link for patients to contact the trial sponsor to ask about trial eligibility and enrollment and links to general information about stem cell trials on the CIRM website and from other organizations.

You can learn more about specific CIRM-funded trials by clicking the “Detail” icon on the Dashboard.

With our new Clinical Dashboard, we hope to raise the visibility of CIRM’s expanding clinical trial portfolio and to provide an all-in-one resource that is useful for multiple audiences.

Dr. Maria Millan, President and CEO of CIRM, concluded:

“CIRM is a global leader in funding high-quality stem cell trials for patients. We created the Clinical Dashboard for our website so that people can easily access important information about CIRM-funded trials and the promising treatments they are testing. As our Agency continues to fund new trials, we hope the Clinical Dashboard will prove to be an invaluable resource for patients, the public, and the stem cell research community.”