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.

cherqui

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”.

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CIRM-Funded Clinical Trials Targeting Brain and Eye Disorders

This blog is part of our Month of CIRM series, which features our Agency’s progress towards achieving our mission to accelerate stem cell treatments to patients with unmet medical needs.

 This week, we’re highlighting CIRM-funded clinical trials to address the growing interest in our rapidly expanding clinical portfolio. Our Agency has funded a total of 40 trials since its inception. 23 of these trials were funded after the launch of our Strategic Plan in 2016, bringing us close to the half way point of our goal to fund 50 new clinical trials by 2020.

Today we are featuring CIRM-funded trials in our neurological and eye disorders portfolio.  CIRM has funded a total of nine trials targeting these disease areas, and seven of these trials are currently active. Check out the infographic below for a list of our currently active trials.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

Stem Cell Stories that Caught our Eye: CRISPRing Human Embryos, brain stem cells slow aging & BrainStorm ALS trial joins CIRM Alpha Clinics

Here are the stem cell stories that caught our eye this week. Enjoy!

Scientists claim first CRISPR editing of human embryos in the US.

Here’s the big story this week. Scientists from Portland, Oregon claim they genetically modified human embryos using the CRISPR/Cas9 gene editing technology. While their results have yet to be published in a peer review journal (though the team say they are going to be published in a prominent journal next month), if they prove true, the study will be the first successful attempt to modify human embryos in the US.

A representation of an embryo being fertilized. Scientists can inject CRISPR during fertilization to correct genetic disorders. (Getty Images).

Steve Connor from MIT Technology Review broke the story earlier this week noting that the only reports of human embryo modification were published by Chinese scientists. The China studies revealed troubling findings. CRISPR caused “off-target” effects, a situation where the CRISPR machinery randomly introduces genetic errors in a cell’s DNA, in the embryos. It also caused mosaicism, a condition where the desired DNA sequences aren’t genetically corrected in all the cells of an embryo producing an individual with cells that have different genomes. Putting aside the ethical conundrum of modifying human embryos, these studies suggested that current gene editing technologies weren’t accurate enough to safely modify human embryos.

But a new chapter in human embryo modification is beginning. Shoukhrat Mitalipov (who is a member of CIRM’s Grants Working Group, the panel of scientific experts that reviews our funding applications) and his team from the Oregon Health and Science University said that they have developed a method to successfully modify donated human embryos that avoids the problems experienced by the Chinese scientists. The team found that introducing CRISPR at the same time an embryo was being fertilized led to successful correction of disease-causing mutations while avoiding mosaicism and “off-target” effects. They grew these embryos for a few days to confirm that the genetic modifications had worked before destroying them.

The MIT piece quoted a scientist who knows of Mitalipov’s work,

“It is proof of principle that it can work. They significantly reduced mosaicism. I don’t think it’s the start of clinical trials yet, but it does take it further than anyone has before.”

Does this discovery, if it’s true, open the door further for the creation of designer babies? For discussions about the future scientific and ethical implications of this research, I recommend reading Paul Knoepfler’s blog, this piece by Megan Molteni in Wired Magazine and Jessica Berg’s article in The Conversation.

Brain stem cells slow aging in mice

The quest for eternal youth might be one step closer thanks to a new study published this week in the journal Nature. Scientists from the Albert Einstein College of Medicine in New York discovered that stem cells found in an area of the brain called the hypothalamus can slow the aging process in mice.

The hypothalamus is located smack in the center of your brain near the brain stem. It’s responsible for essential metabolic functions such as making and secreting hormones, managing body temperature and controlling feelings of hunger and thirst. Because the body’s metabolic functions decline with age, scientists have suspected that the hypothalamus plays a role in aging.

The mouse hypothalamus. (NIH, Wikimedia).

In the current study, the team found that stem cells in the hypothalamus gradually disappear as mice age. They were curious whether the disappearance of these stem cells could jump start the aging process. When they removed these stem cells, the mice showed more advanced mental and physical signs of aging compared to untreated mice.

They also conducted the opposite experiment where they transplanted hypothalamic stem cells taken from baby mice (the idea being that these stem cells would exhibit more “youthful” qualities) into the brains of middle-aged mice and saw improvements in mental and physical functions and a 10% increase in lifespan.

So what is it about these specific stem cells that slows down aging? Do they replenish the aging brain with new healthy cells or do they secrete factors that keep the brain healthy? Interestingly, the scientists found that these stem cells secreted vesicles that contained microRNAs, which are molecules that regulate gene expression by turning genes on or off.

They injected these microRNAs into the brains of middle-aged mice and found that they reversed symptoms of aging including cognitive decline and muscle degeneration. Furthermore, when they removed hypothalamic stem cells from middle-aged mice and treated them with the microRNAs, they saw the same anti-aging effects.

In an interview with Nature News, senior author on the study, Dongsheng Cai, commented that hypothalamic stem cells could have multiple ways of regulating aging and that microRNAs are just one of their tools. For this research to translate into an anti-aging therapy, “Cai suspects that anti-ageing therapies targeting the hypothalamus would need to be administered in middle age, before a person’s muscles and metabolism have degenerated beyond a point that could be reversed.”

This study and its “Fountain of Youth” implications has received ample attention from the media. You can read more coverage from The Scientist, GenBio, and the original Albert Einstein press release.

BrainStorm ALS trial joins the CIRM Alpha Clinics

Last month, the CIRM Board approved $15.9 million in funding for BrainStorm Cell Therapeutic’s Phase 3 trial that’s testing a stem cell therapy to treat patients with a devastating neurodegenerative disease called amyotrophic lateral sclerosis or ALS (also known as Lou Gehrig’s disease).

The stem cell therapy, called NurOwn®, is made of mesenchymal stem cells extracted from a patient’s bone marrow. The stem cells are genetically modified to secrete neurotrophic factors that keep neurons in the brain healthy and prevent their destruction by diseases like ALS.

BrainStorm has tested NurOwn in early stage clinical trials in Israel and in a Phase 2 study in the US. These trials revealed that the treatment was “safe and well tolerated” and that “NurOwn also achieved multiple secondary efficacy endpoints, showing clear evidence of a clinically meaningful benefit.  Notably, response rates were higher for NurOwn-treated subjects compared to placebo at all time points in the study out to 24 weeks.”

This week, BrainStorm announced that it will launch its Phase 3 CIRM-funded trial at the UC Irvine (UCI) CIRM Alpha Stem Cell Clinic. The Alpha Clinics are a network of top medical centers in California that specialize in delivering high quality stem cell clinical trials to patients. UCI is one of four medical centers including UCLA, City of Hope, and UCSD, that make up three Alpha Clinics currently supporting 38 stem cell trials in the state.

Along with UCI, BrainStorm’s Phase 3 trial will also be conducted at two other sites in the US: Mass General Hospital in Boston and California Pacific Medical Center in San Francisco. Chaim Lebovits, President and CEO, commented,

“We are privileged to have UCI and Dr. Namita Goyal join our pivotal Phase 3 study of NurOwn. Adding UCI as an enrolling center with Dr. Goyal as Principal Investigator will make the treatment more accessible to patients in California, and we welcome the opportunity to work with this prestigious institution.”

Before the Phase 3 trial can launch at UCI, it needs to be approved by our federal regulatory agency, the Food and Drug Administration (FDA), and an Institutional Review Board (IRB), which is an independent ethics committee that reviews biomedical research on human subjects. Both these steps are required to ensure that a therapy is safe to test in patients.

With promising data from their Phase 1 and 2 trials, BrainStorm’s Phase 3 trial will likely get the green light to move forward. Dr. Goyal, who will lead the trial at the UCI Alpha Clinic, concluded:

“NurOwn is a very promising treatment with compelling Phase 2 data in patients with ALS; we look forward to further advancing it in clinical development and confirming the therapeutic benefit with Brainstorm.”

Stem cell agency funds Phase 3 clinical trial for Lou Gehrig’s disease

ALS

At CIRM we don’t have a disease hierarchy list that we use to guide where our funding goes. We don’t rank a disease by how many people suffer from it, if it affects children or adults, or how painful it is. But if we did have that kind of hierarchy you can be sure that Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, would be high on that list.

ALS is a truly nasty disease. It attacks the neurons, the cells in our brain and spinal cord that tell our muscles what to do. As those cells are destroyed we lose our ability to walk, to swallow, to talk, and ultimately to breathe.

As Dr. Maria Millan, CIRM’s interim President and CEO, said in a news release, it’s a fast-moving disease:

“ALS is a devastating disease with an average life expectancy of less than five years, and individuals afflicted with this condition suffer an extreme loss in quality of life. CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and, in keeping with this mission, our objective is to find a treatment for patients ravaged by this neurological condition for which there is currently no cure.”

Having given several talks to ALS support groups around the state, I have had the privilege of meeting many people with ALS and their families. I have seen how quickly the disease works and the devastation it brings. I’m always left in awe by the courage and dignity with which people bear it.

BrainStorm

I thought of those people, those families, today, when our governing Board voted to invest $15.9 million in a Phase 3 clinical trial for ALS run by BrainStorm Cell Therapeutics. BrainStorm is using mesenchymal stem cells (MSCs) that are taken from the patient’s own bone marrow. This reduces the risk of the patient’s immune system fighting the therapy.

After being removed, the MSCs are then modified in the laboratory to  boost their production of neurotrophic factors, proteins which are known to help support and protect the cells destroyed by ALS. The therapy, called NurOwn, is then re-infused back into the patient.

In an earlier Phase 2 clinical trial, NurOwn showed that it was safe and well tolerated by patients. It also showed evidence that it can help stop, or even reverse  the progression of the disease over a six month period, compared to a placebo.

CIRM is already funding one clinical trial program focused on treating ALS – that’s the work of Dr. Clive Svendsen and his team at Cedars Sinai, you can read about that here. Being able to add a second project, one that is in a Phase 3 clinical trial – the last stage before, hopefully, getting approval from the Food and Drug Administration (FDA) for wider use – means we are one step closer to being able to offer people with ALS a treatment that can help them.

Diane Winokur, the CIRM Board Patient Advocate member for ALS, says this is something that has been a long time coming:

CIRM Board member and ALS Patient Advocate Diane Winokur

“I lost two sons to ALS.  When my youngest son was diagnosed, he was confident that I would find something to save him.  There was very little research being done for ALS and most of that was very limited in scope.  There was one drug that had been developed.  It was being released for compassionate use and was scheduled to be reviewed by the FDA in the near future.  I was able to get the drug for Douglas.  It didn’t really help him and it was ultimately not approved by the FDA.

When my older son was diagnosed five years later, he too was convinced I would find a therapy.  Again, I talked to everyone in the field, searched every related study, but could find nothing promising.

I am tenacious by nature, and after Hugh’s death, though tempted to give up, I renewed my search.  There were more people, labs, companies looking at neurodegenerative diseases.

These two trials that CIRM is now funding represent breakthrough moments for me and for everyone touched by ALS.  I feel that they are a promising beginning.  I wish it had happened sooner.  In a way, though, they have validated Douglas and Hugh’s faith in me.”

These therapies are not a cure for ALS. At least not yet. But what they will do is hopefully help buy people time, and give them a sense of hope. For a disease that leaves people desperately short of both time and hope, that would be a precious gift. And for people like Diane Winokur, who have fought so hard to find something to help their loved ones, it’s a vindication that those efforts have not been in vain.