CIRM’s Randy Mills leaving stem cell agency to take on new challenge

Mills, Randy Union Tribune K.C. Alfred

Some news releases are fun to write. Some less so. The one that CIRM posted today definitely falls into that latter group. It announced that CIRM’s President and CEO, Randy Mills, is leaving us to take up the role of President and CEO at the National Marrow Donor Program – NMPD/Be The Match.

It’s a great opportunity for him but a big loss for us.

Be The Match is a non-profit organization that delivers cures to patients in need of a life-saving marrow or cord blood transplant. The organization operates the national Be The Match Registry®—the world’s largest listing of potential marrow donors and donated umbilical cord blood units—matches patients with their marrow donor, educates healthcare professionals and conducts research so more lives can be saved. The organization also recently created a subsidiary—Be The Match BioTherapiesSM—that supports organizations pursuing new life-saving treatments in cellular therapy.

Randy has been at CIRM since April 2014. In that time he has dramatically re-shaped the agency, and, more importantly, dramatically improved the speed with which we are able to fund research. It’s no exaggeration to say that Randy’s drive to create CIRM 2.0 was a radical overhaul of the way we work. It made it easier for researchers to apply to us for funding, made our funding cycles more consistent and the application process simpler – though no less rigorous.

As our CIRM Board Chair Jonathan Thomas said in the news release:

“CIRM has experienced a remarkable transformation since Randy’s arrival. He has taken the agency to a new level by developing and implementing a bold strategic plan, the results of which include an 82% reduction in approval time for clinical trial projects, a 3-fold increase in the number of clinical trials, and a 65% reduction in the time it takes to enroll those trials. The opportunity for Randy to lead a tremendously important organization such as the NMDP/Be The Match is consistent with the values he demonstrated at CIRM, which put the well-being of patients above all else. We shall miss him but know he will do great things at NMDP/Be The Match.”

From a personal perspective, what most impressed me about Randy was his willingness to involve every person in the agency in changing the way we work. He could easily have come in and simply issued orders and told people what to do. Instead he invited every person at CIRM to sit in on the meetings that were shaping the new direction we took. You didn’t have to go, but if you did you were expected to offer thoughts and ideas. No sitting idly by.

Those meetings not only changed the direction of the agency, they also re-energized the agency. When people feel their voice is being heard, that their opinion has value, they respond by working harder and smarter.

The CIRM of today has the same mission as always – accelerating stem cell treatments to patients with unmet medical needs – but the people working here seem to have a renewed commitment to making that mission a reality.

Randy brought to CIRM energy and a renewed sense of purpose, along with some truly terrible jokes and a strange conviction that he could have been a great rock and roll drummer (suffice to say he made the right career choice when he went into research).

He changed us as an agency, for the better. We shall miss him, but know he will do great things in his new role at NMDP/Be The Match and we wish him success in his new job, and his family great joy in their new home.

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Maria Millan

Randy will be with us till the end of June and starting July 1st Dr. Maria Millan will take on the role of interim President and CEO.

 

 

 

The power of the patient’s voice: how advocates shape clinical trials and give hope to those battling deadly diseases

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The Stack family: L to R Alex, Natalie, Nancy & Jeff

Tennis great Martina Navratilova was once being interviewed about what made her such a great competitor and she said it was all down to commitment. When pressed she said “the difference between involvement and commitment is like ham and eggs; the chicken is involved but the pig is committed.”

That’s how I feel about the important role that patients and patient advocates play in the work that we do at CIRM. Those of us who work here are involved. The patients and patient advocates are committed. This isn’t just their life’s work;  it’s their life.

I was reminded of that last week when I had the privilege of talking with Nancy Stack, the Patient Representative on a Clinical Advisory Panel (CAP) we have created for a program to treat cystinosis. She has an amazing story to tell. But before we get to that I have to do a little explaining.

Cystinosis is a rare disease, affecting maybe only 2,000 people worldwide, that usually strikes children before they are two years old and can lead to end stage kidney failure before their tenth birthday. Current treatments are limited, which is why the average life expectancy for someone with this is only around 27 years.

When we fund a project that is already in, or hoping to be in, a clinical trial we create a CAP to help assist the team behind the research. The CAP consists of a CIRM Science Officer, an independent scientific expert in this case for cystinosis, and a Patient Representative.

The patient’s voice

The Patient Representative’s role is vital because they can help the researchers understand the needs of the patient and take those needs into account when designing the trial. In the past, many researchers had little contact with patients and so designed the trial around their own needs. The patients had to fit into that model. We think it should be the other way around; that the model should fit the patients. The Patient Representatives help us make that happen.

Nancy Stack did just that. At the first meeting of the CAP she showed up with a list of 38 questions that she and other families with cystinosis had come up with for the researchers. They went from the blunt – “Will I die from the treatment” – to the practical –  “How will children/teens keep up with school during the process?” – and included a series of questions from a 12-year old girl with the disease – “Will I lose my hair because I’ve been growing it out for a long time? Will I feel sick? Will it hurt?”

Nancy says the questions are not meant to challenge the researcher, in this case U.C. San Diego’s Stephanie Cherqui, but to ensure that if the trial is given the go-ahead by the US Food and Drug Administration (FDA) that every patient who signs up for it knows exactly what they are getting into. That’s particularly important because many of those could be children or teenagers.

Fully informed

“As parents we know the science is great and is advancing, but we have real people who are going to go through this treatment so we have a responsibility to know what will it mean to them. Patients know they could die of the disease and so this research has real world implications for them.”

“I think without this, without allowing the patients voice to be heard, you would have a hard time recruiting patients for this kind of clinical trial.”

Nancy says not only was Dr. Cherqui not surprised by the questions, she welcomed them. Dr. Cherqui has been supported and funded by the Cystinosis Research Foundation for years and Nancy says she regards the patients and patient advocates as partners in this journey:

“She knows we are not challenging her, we’re supporting her and helping her cover every aspect of the research to help make it work.”

Nancy became committed to finding a cure for cystinosis when her daughter, Natalie, was diagnosed with the condition when she was just 7 months old. The family were handed a pamphlet titled “What to do when your child has a terminal disease” and told there was no cure.

Birthday wish

In 2003, on the eve of her 12th birthday, Nancy asked Natalie what her wish was for her birthday. She wrote on a napkin “to have my disease go away forever.” The average life expectancy for people with cystinosis at that point was 18. Nancy told her husband “We have to do something.”

They launched the Cystinosis Research Foundation and a few weeks later they held their first fundraiser. That first year they raised $427,000, an impressive amount for such a rare disease. Last year they raised $4.94 million. Every penny of that $4.94 million goes towards research, making them the largest funders of cystinosis research in the world.

“We learned that for there to be hope there has to be research, and to do research we needed to raise funds. Without that we knew our children would not survive this disease.”

Natalie is now 26, a graduate of Georgetown and USC, and about to embark on a career in social work. Nancy knows many others are not so fortunate:

“Every year we lose some of our adults, even some of our teens, and that is unbelievably hard. Those other children, wherever they may live, they are my children too. We are all connected to each other and that’s what motivates me every day. Having a child with this disease means that time is running out and there must be a commitment to work hard every day to find a cure, and never giving up until you do.”

That passion for the cause, that compassion for others and determination to help others makes the Patient Representative on the CAP so important. They are a reminder that we all need to work as hard as we can, as fast as we can, and do everything we can to help these trials succeed.

And we are committed to doing that.


Related Links:

Stem Cell Profiles in Courage: Brenden Whittaker

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Brenden Whittaker: Photo Colin McGuire

It’s not often you meet someone who says one of their favorite things in the world is mowing the lawn. But then, there aren’t many people in the world like Brenden Whittaker. In fact, as of this writing, he may be unique.

Brenden was born with severe chronic granulomatous disease (x-CGD), a rare genetic disorder that left him with an impaired immune system that was vulnerable to repeated bacterial and fungal infections. Over 22 years Brenden was in and out of the hospital hundreds of times, he almost died a couple of times, and lost parts of his lungs and liver.

Then he became the first person to take part in a clinical trial to treat x-CGD. UCLA researcher Don Kohn had developed a technique that removed Brenden’s blood stem cells, genetically re-engineered them to correct the mutation that caused the disease, and then returned those stem cells to Brenden. Over time they created a new blood system, and restored Brenden’s immune system.

He was cured.

We profiled Brenden for our 2016 Annual Report. Here’s an extended version of the interview we did with him, talking about his life before and after he was cured.

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Brenden with a CIRM Game Ball – signed by everyone at CIRM

Brenden’s story:

I still think about it, my disease, every few days or so and it’s weird because in the past I was sick so often; before this year, I was sick consistently for about 5 years and going to doctor’s appointments 2 or 3 times a week and being in the hospital. So, it’s weird having a cough and not having to be rushed to the ER, not having to call someone every time the smallest thing pops up, and not having to worry about what it means.

It’s been good but it’s been weird to not have to do that.  It’s a nice problem to have.

What are you doing now that you didn’t do before?

Cutting the grass is something I couldn’t do before, that I’ve taken up now. Most people look at me as if I’m crazy when I say it, but I love cutting grass, and I wasn’t able to do it for 22 years of my life.

People will complain about having to pick up after their dog goes to the bathroom and now I can follow my dog outside and can pick up after her. It really is just the little things that people don’t think of. I find enjoyment in the small things, things I couldn’t do before but now I can and not have to worry about them.

The future

I was in the boy scouts growing up so I love camping, building fires, just being outdoors. I hiked on the Appalachian Trail. Now I’ll be able to do more of that.

I have a part time job at a golf course and I’m actually getting ready to go back to school full time in January. I want to get into pre-med, go to medical school and become a doctor. All the experience I’ve had has just made me more interested in being a doctor, I just want to be in a position where I can help people going through similar things, and going through all this just made me more interested in it.

Before the last few months I couldn’t schedule my work more than a week in advance because I didn’t know if I was going to be in the hospital or what was going on. Now my boss jokes that I’m giving him plans for the next month or two. It’s amazing how far ahead you can plan when you aren’t worried about being sick or having to go to the hospital.

I’d love to do some traveling. Right now most of my traveling consists of going to and from Boston (for medical check-ups), but I would love to go to Europe, go through France and Italy. That would be a real cool trip. I don’t need to see everything in the world but just going to other countries, seeing cities like London, Paris and Rome, seeing how people live in other cultures, that would be great.

Advice for others

I do think about the fact that when I was born one in a million kids were diagnosed with this disease and there weren’t any treatments. Many people only lived a few years. But to be diagnosed now you can have a normal life. That’s something all on its own. It’s almost impossible for me to fathom it’s happening, after all the years and doctor’s appointments and illnesses.

So, for people going through anything like this, I’d say just don’t give up. There are new advances being made every day and you have to keep fighting and keep getting through it, and some day it will all work out.


Related Links:

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

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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.

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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.

 

 

 

 

Key Steps Along the Way To Finding Treatments for HIV on World AIDS Day

Today, December 1st,  is World AIDS Day. It’s a day to acknowledge the progress that is being made in HIV prevention and treatment around the world but also to renew our commitment to a future free of HIV. This year’s theme is Leadership. Commitment. Impact.  At CIRM we are funding a number of projects focused on HIV/AIDS, so we asked Jeff Sheehy, the patient advocate for HIV/AIDS on the CIRM Board to offer his perspective on the fight against the virus.

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At CIRM we talk about and hope for cures, but our actual mission is “accelerating stem cell treatments to patients with unmet medical needs.”

For those of us in the HIV/AIDS community, we are tremendously excited about finding a cure for HIV.  We have the example of Timothy Brown, aka the “Berlin Patient”, the only person cured of HIV.

Multiple Shots on Goal

Different approaches to a cure are under investigation with multiple clinical trials.  CIRM is funding three clinical trials using cell/gene therapy in attempts to genetically modify blood forming stem cells to resist infection with HIV.  While we hope this leads to a cure, community activists have come together to urge a look at something short of a “home run.”

A subset of HIV patients go on treatment, control the virus in their blood to the point where it can’t be detected by common diagnostic tests, but never see their crucial immune fighting CD4 T cells return to normal levels after decimation by HIV.

For instance, I have been on antiretroviral therapy since 1997.  My CD4 T cells had dropped precipitously, dangerous close to the level of 200.  At that level, I would have had an AIDS diagnosis and would have been extremely vulnerable to a whole host of opportunistic infections.  Fortunately, my virus was controlled within a few weeks and within a year, my CD T cells had returned to normal levels.

For the immunological non-responders I described above, that doesn’t happen.  So while the virus is under control, their T cell counts remain low and they are very susceptible to opportunistic infections and are at much greater risk of dying.

Immunological non-responders (INRs) are usually patients who had AIDS when they were diagnosed, meaning they presented with very low CD4 T cell counts.  Many are also older.  We had hoped that with frequent testing, treatment upon diagnosis and robust healthcare systems, this population would be less of a factor.  Yet in San Francisco with its very comprehensive and sophisticated testing and treatment protocols, 16% of newly diagnosed patients in 2015 had full blown AIDS.

Until we make greater progress in testing and treating people with HIV, we can expect to see immunological non-responders who will experience sub-optimal health outcomes and who will be more difficult to treat and keep alive.

Boosting the Immune System

A major cell/gene trial for HIV targeted this population.  Their obvious unmet medical need and their greater morbidity/mortality balanced the risks of first in man gene therapy.  Sangamo, a CIRM grantee, used zinc finger nucleases to snip out a receptor, CCR5, on the surface of CD4 T cells taken from INR patients.  That receptor is a door that HIV uses to enter cells.  Some people naturally lack the receptor and usually are unable to be infected with HIV.  The Berlin Patient had his entire immune system replaced with cells from someone lacking CCR5.

Most of the patients in that first trial saw their CD4 T cells rise sharply.  The amount of HIV circulating in their gut decreased.  They experienced a high degree of modification and persistence in T stem cells, which replenish the T cell population.  And most importantly, some who regularly experienced opportunistic infections such as my friend and study participant Matt Sharp who came down with pneumonia every winter, had several healthy seasons.

Missed Opportunities

Unfortunately, the drive for a cure pushed development of the product in a different direction.  This is in large part to regulatory challenges.  A prior trial started in the late 90’s by Chiron tested a cytokine, IL 2, to see if administering it could increase T cells.  It did, but proving that these new T cells did anything was illusive and development ceased.  Another cytokine, IL 7, was moving down the development pathway when the company developing it, Cytheris, ceased business.  The pivotal trial would have required enrolling 4,000 participants, a daunting and expensive prospect.  This was due to the need to demonstrate clinical impact of the new cells in a diverse group of patients.

Given the unmet need, HIV activists have looked at the Sangamo trial, amongst others, and have initiated a dialogue with the FDA.  Activists are exploring seeking orphan drug status since the population of INRs is relatively small.

Charting a New Course

They have also discussed trial designs looking at markers of immune activity and discussed potentially identifying a segment of INRs where clinical efficacy could be shown with far, far fewer participants.

Activists are calling for companies to join them in developing products for INRs.  I’ve included the press release issued yesterday by community advocates below.

With the collaboration of the HIV activist community, this could be a unique opportunity for cell/gene companies to actually get a therapy through the FDA. On this World AIDS Day, let’s consider the value of a solid single that serves patients in need while work continues on the home run.

NEWS RELEASE: HIV Activists Seek to Accelerate Development of Immune Enhancing Therapies for Immunologic Non-Responders.

Dialogues with FDA, scientists and industry encourage consideration of orphan drug designations for therapies to help the immunologic non-responder population and exploration of novel endpoints to reduce the size of efficacy trials.

November 30, 2016 – A coalition of HIV/AIDS activists are calling for renewed attention to HIV-positive people termed immunologic non-responders (INRs), who experience sub-optimal immune system reconstitution despite years of viral load suppression by antiretroviral therapy. Studies have shown that INR patients remain at increased risk of illness and death compared to HIV-positive people who have better restoration of immune function on current drug therapies. Risk factors for becoming an INR include older age and a low CD4 count at the time of treatment initiation. To date, efforts to develop immune enhancing interventions for this population have proven challenging, despite some candidates from small companies showing signs of promise.

“We believe there is an urgent need to find ways to encourage and accelerate development of therapies to reduce the health risks faced by INR patients,” stated Nelson Vergel of the Program for Wellness Restoration (PoWeR), who initiated the activist coalition. “For example, Orphan Drug designations[i] could be granted to encourage faster-track approval of promising therapies.  These interventions may eventually help not only INRs but also people with other immune deficiency conditions”.

Along with funding, a major challenge for approval of any potential therapy is proving its efficacy. While INRs face significantly increased risk of serious morbidities and mortality compared to HIV-positive individuals with more robust immune reconstitution, demonstrating a reduction in the incidence of these outcomes would likely require expensive and lengthy clinical trials involving thousands of individuals. Activists are therefore encouraging the US Food & Drug Administration (FDA), industry and researchers to evaluate potential surrogate markers of efficacy such as relative improvements in clinical problems that may be more frequent in INR patients, such as upper respiratory infections, gastrointestinal disease, and other health issues.

“Given the risks faced by INR patients, every effort should be made to assess whether less burdensome pathways toward approval are feasible, without compromising the regulatory requirement for compelling evidence of safety and efficacy”, said Richard Jefferys of the Treatment Action Group.

The coalition is advocating that scientists, biotech and pharmaceutical companies pursue therapeutic candidates for INRs. For example, while gene and anti-inflammatory therapies for HIV are being assessed in the context of cure research, there is also evidence that they may have potential to promote immune reconstitution and reduce markers associated with risk of morbidity and mortality in INR patients. Therapeutic research should also be accompanied by robust study of the etiology and mechanisms of sub-optimal immune responses.

“While there is, appropriately, a major research focus on curing HIV, we must be alert to evidence that candidate therapies could have benefits for INR patients, and be willing to study them in this context”, argued Matt Sharp, a coalition member and INR who experienced enhanced immune reconstitution and improved health and quality of life after receiving an experimental gene therapy.

The coalition has held an initial conference call with FDA to discuss the issue. Minutes are available online.

The coalition is now aiming to convene a broader dialogue with various drug companies on the development of therapies for INR patients. Stakeholders who are interested in becoming involved are encouraged to contact coalition representatives.

[i] The Orphan Drug Act incentivizes the development of treatments for rare conditions. For more information, see:  http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/ucm2005525.htm

For more information:

Richard Jefferys

Michael Palm Basic Science, Vaccines & Cure Project Director
Treatment Action Group richard.jefferys@treatmentactiongroup.org

Nelson Vergel, Program for Wellness Restoration programforwellness@gmail.com

 

 

Creating a “Pitching Machine” to speed up our delivery of stem cell treatments to patients

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When baseball players are trying to improve their hitting they’ll use a pitching machine to help them fine tune their stroke. Having a device that delivers a ball at a consistent speed can help a batter be more consistent and effective in their swing, and hopefully get more hits.

That’s what we are hoping our new Translating and Accelerating Centers will do. We call these our “Pitching Machine”, because we hope they’ll help researchers be better prepared when they apply to the Food and Drug Administration (FDA) for approval to start a clinical trial, and be more efficient and effective in the way they set up and run that clinical trial once they get approval.

The CIRM Board approved the Accelerating Center earlier this summer. The $15 million award went to QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider.

The Accelerating Center will provide key core services for researchers who have been given approval to run a clinical trial, including:

  • Regulatory support and management services
  • Clinical trial operations and management services
  • Data management, biostatistical and analytical services

The reason why these kinds of service are needed is simple, as Randy Mills, our President and CEO explained at the time:

“Many scientists are brilliant researchers but have little experience or expertise in navigating the regulatory process; this Accelerating Center means they don’t have to develop those skills; we provide them for them.”

The Translating Center is the second part of the “Pitching Machine”. That is due to go to our Board for a vote tomorrow. This is an innovative new center that will support the stem cell research, manufacturing, preclinical safety testing, and other activities needed to successfully apply to the FDA for approval to start a clinical trial.

The Translating Center will:

  • Provide consultation and guidance to researchers about the translational process for their stem cell product.
  • Initiate, plan, track, and coordinate activities necessary for preclinical Investigational New Drug (IND)-enabling development projects.
  • Conduct preclinical research activities, including pivotal pharmacology and toxicology studies.
  • Manufacture stem cell and gene modified stem cell products under the highest quality standards for use in preclinical and clinical studies.

The two centers will work together, helping researchers create a comprehensive development plan for every aspect of their project.

For the researchers this is important in giving them the support they need. For the FDA it could also be useful in ensuring that the applications they get from CIRM-funded projects are consistent, high quality and meet all their requirements.

We want to do everything we can to ensure that when a CIRM-funded therapy is ready to start a clinical trial that its application is more likely to be a hit with the FDA, and not to strike out.

Just as batting practice is crucial to improving performance in baseball, we are hoping our “Pitching Machine” will raise our game to the next level, and enable us to deliver some game-changing treatments to patients with unmet medical needs.

 

Funding stem cell research targeting a rare and life-threatening disease in children

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Photo courtesy Cystinosis Research Network

If you have never heard of cystinosis you should consider yourself fortunate. It’s a rare condition caused by an inherited genetic mutation. It hits early and it hits hard. Children with cystinosis are usually diagnosed before age 2 and are in end-stage kidney failure by the time they are 9. If that’s not bad enough they also experience damage to their eyes, liver, muscles, pancreas and brain.

The genetic mutation behind the condition results in an amino acid, cystine, accumulating at toxic levels in the body. There’s no cure. There is one approved treatment but it only delays progression of the disease, has some serious side effects of its own, and doesn’t prevent the need for a  kidney transplant.

Researchers at UC San Diego, led by Stephanie Cherqui, think they might have a better approach, one that could offer a single, life-long treatment for the problem. Yesterday the CIRM Board agreed and approved more than $5.2 million for Cherqui and her team to do the pre-clinical testing and work needed to get this potential treatment ready for a clinical trial.

Their goal is to take blood stem cells from people with cystinosis, genetically-modify them and return them to the patient, effectively delivering a healthy, functional gene to the body. The hope is that these genetically-modified blood stem cells will integrate with various body organs and not only replace diseased cells but also rescue them from the disease, making them healthy once again.

In a news release Randy Mills, CIRM’s President and CEO, said orphan diseases like cystinosis may not affect large numbers of people but are no less deserving of research in finding an effective therapy:

“Current treatments are expensive and limited. We want to push beyond and help find a life-long treatment, one that could prevent kidney failure and the need for kidney transplant. In this case, both the need and the science were compelling.”

The beauty of work like this is that, if successful, a one-time treatment could last a lifetime, eliminating or reducing kidney disease and the need for kidney transplantation. But it doesn’t stop there. The lessons learned through research like this might also apply to other inherited multi-organ degenerative disorders.

Asterias’ stem cell clinical trial shows encouraging results for spinal cord injury patients

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Jake Javier; Asterias spinal cord injury clinical trial participant

When researchers are carrying out a clinical trial they have two goals: first, show that it is safe (the old “do no harm” maxim) and second, show it works. One without the other doesn’t do anyone any good in the long run.

A few weeks ago Asterias Biotherapeutics showed that their CIRM-funded stem cell therapy for spinal cord injuries appeared to be safe. Now their data suggests it’s working. And that is a pretty exciting combination.

Asterias announced the news at the annual scientific meeting of the International Spinal Cord Society in Vienna, Austria. These results cover five people who got a transplant of 10 million cells. While the language is muted, the implications are very encouraging:

“While early in the study, with only 4 of the 5 patients in the cohort having reached 90 days after dosing, all patients have shown at least one motor level of improvement so far and the efficacy target of 2 of 5 patients in the cohort achieving two motor levels of improvement on at least one side of their body has already been achieved.”

What does that mean for the people treated? A lot. Remember these are people who qualified for this clinical trial because of an injury that left them pretty much paralyzed from the chest down. Seeing an improvement of two motor levels means they are regaining some use of their arms, hands and fingers, and that means they are regaining the ability to do things like feeding, dressing and bathing themselves. In effect, it is not only improving their quality of life but it is also giving them a chance to lead an independent life.

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Kris Boesen, Asterias clinical trial participant

One of those patients is Kris Boesen who regained the use of his arms and hands after becoming the first patient in this trial to get a transplant of 10 million cells. We blogged about Kris here

Asterias says of the 5 patients who got 10 million cells, 4 are now 90 days out from their transplant. Of those:

  • All four have improved one motor level on at least one side
  • 2 patients have improved two motor levels on one side
  • One has improved two motor levels on both sides

What’s also encouraging is that none of the people treated experienced any serious side effects or adverse events from the transplant or the temporary use of immunosuppressive drugs.

Steve Cartt, CEO of Asterias, was understandably happy with the news and that it allows them to move to the next phase:

“We are quite encouraged by this first look at efficacy results and look forward to reporting six-month efficacy data as planned in January 2017.  We have also just recently been cleared to begin enrolling a new cohort and administering to these new patients a much higher dose of 20 million cells.  We look forward to begin evaluating efficacy results in this higher-dose cohort in the coming months as well.”

People with spinal cord injuries can regain some function spontaneously so no one is yet leaping to the conclusion that all the progress in this trial is due to the stem cells. But to see all of the patients in the 10 million stem cell group do well is at the very least a positive sign. Now the hope is that these folks will continue to do well, and that the next group of people who get a 20 million cell transplant will also see improvements.

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Roman Reed, spinal cord injury patient advocate

While the team at Asterias were being cautiously optimistic, Roman Reed, whose foundation helped fund the early research that led to this clinical trial, was much less subdued in his response. He was positively giddy:

“If one patient only improves out of the five, it can be an outlier, but with everyone improving out of the five this is legit, this is real. Cures are happening!”

 

CIRM’s Randy Mills: New FDA rules for stem cells won’t fix the problem

For the last two days the Food and Drug Administration (FDA) has been holding a hearing in Bethesda, Maryland on new regulations that would tighten control over stem cell treatments. The FDA invited public testimony during the hearing on the regulations that would impact many of the clinics that currently offer unproven therapies

The testimony has been impassioned to say the least. Supporters of the clinics say they offer a valuable service and that patients should be allowed to decide for themselves how they want their own cells to be used. Opponents say the clinics are little more than snake oil sales people, offering bogus, unproven treatments.

One of those presenting was Randy Mills, CIRM’s President and CEO. Randy has been very vocal in the past about the need for the FDA to change the way it regulates stem cell therapies.

In California Healthline Randy explained why he thinks the rules the FDA is proposing will not fix the problem, and may even make it worse:

FDA Must Find A Middle Ground For Sake Of Patients

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Randy Mills

We aren’t happy, as a lot of people aren’t happy, with the proliferation of these stem cell clinics — some of which are probably doing good work. But some are clearly making rather outlandish claims for which there’s no real data. 

There are a couple of conditions coming together to create this storm.

One is that the need is very real. These patients are really struggling. They don’t have alternatives. They’re desperate and they need help. It’s not in the realm of possibility to talk to somebody who is suffering as badly as these patients are and to say, ‘You have to wait a few more decades for the science to catch up.’

On the other hand, we have a regulatory paradigm that only provides two pathways to put a cell therapy onto the market. One pathway is the most intense regulatory requirement anywhere in the world for any product — the biologics license application through the FDA, which takes 10 to 20 years and costs over $1 billion.

The other is through the exemptions the FDA has made, which require absolutely no pre-market approval whatsoever. You can be on the market in days, with no data.

The regulatory burden associated with one is massive and the other is almost nonexistent.

So it’s not at all surprising that we’re seeing a proliferation of these stem cell clinics popping up that are operating under the assumption that they fall under the exemption.

What the FDA is doing now is saying, ‘We’re not happy with this. We’re going to define some terms more narrowly than in the past … and make it more difficult to legally be on the market under the less burdensome regulatory pathway.’

That’s what this meeting is about.

The problem with their strategy is twofold. It doesn’t address the patients, or the need side of the equation. And I don’t think it has a chance of actually working because the FDA will acknowledge that they do not have the resources to enforce these types of regulations at the clinic level.

They would have to be essentially regulating the practice of physicians, which is well beyond their capabilities. Even if they were able to enforce it, it would just drive these patients somewhere else.

We’re advocating for the creation of some middle pathway that would bring essentially unregulated therapies into the regulatory fold, but in a manner which could be complied with.

I would rather know these clinics are being regulated and collecting data than have them operating under the radar screen of the FDA. I would like there to be a formal pre-market review of these therapies before they’re put on the market. I would like there to be safety and efficacy data.

I’m going to try hard to get the FDA to see that just plugging this hole won’t make the problem go away.

Thinking that they’re going to strengthen the regulation and that patients are going to be satisfied that there’s absolutely no chance for help is naive.

There isn’t a lot of evidence to suggest these types of procedures are overly risky. It’s not that they don’t have risk, but everything in medicine does. If you’re a patient who has absolutely no alternative, you’re probably willing to take the chance.

Salk scientists explain why brain cells are genetically diverse

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I’ve always wondered why some sets of genetically identical twins become not so identical later in life. Sometimes they differ in appearance. Other times, one twin is healthy while the other is plagued with a serious disease. These differences can be explained by exposure to different environmental factors over time, but there could also be a genetic explanation involving our brains.

The brain is composed of approximately 100 billion cells called neurons, each with a DNA blueprint that contains instructions that determine the function of these neurons in the brain. Originally it was thought that all cells, including neurons, have the same DNA. But more recently, scientists discovered that the brain is genetically diverse and that neurons within the same brain can have slightly different DNA blueprints, which could give them slightly different functions.

Jumping genes and genetic diversity

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Fred “Rusty” Gage: Photo courtesy Salk Institute

Why and how neurons have differences in their DNA are questions that Salk Institute professor Fred Gage has pursued for more than a decade. In 2005, his lab discovered a mechanism during neural development that causes differences in the DNA of neurons. As a brain stem cell develops into a neuron, long interspersed nuclear elements (L1s), which are small pieces of DNA, copy and paste themselves, seemingly at random, throughout a neuron’s genome.

These elements were originally dubbed “jumping genes” because of their ability to hop around and insert themselves into DNA. It turns out that L1s do more than copy and paste themselves to create changes in DNA, they also can delete chunks of DNA. In a CIRM-funded study published this week in the journal Nature Neuroscience, Gage and colleagues at the Salk Institute reported new insights into L1 activity and how it creates genetic diversity in the brain.

Copy, paste, delete

Gage and his team had clues that L1s can cause DNA deletions in neurons back in 2013. They used a technique called single-cell sequencing to record the sequence of individual neuronal genomes and saw that some of their genomes had large sections of DNA added or missing.

They thought that L1s could be the reason for these insertions and deletions, but didn’t have proof until their current study, which used an improved method to identify areas of the neuronal genome modified by L1s. This method, combined with a computer algorithm that can easily tell the difference between various types of L1 modifications, revealed that areas of the genome with L1s were susceptible to DNA cutting caused by enzymes that home in on the L1 sequences. These breaks in the DNA then cause the observed deletions.

Gage explained their findings in a news release:

“In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person. This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism.”

Jennifer Erwin, first author on the study, further elaborated:

“The surprising part was that we thought all L1s could do was insert into new places. But the fact that they’re causing deletions means that they’re affecting the genome in a more significant way,” says Erwin, a staff scientist in Gage’s group.”

Insights into brain disorders

It’s now known that L1s are important for the brain’s genetic diversity, but Gage also believes that L1s could play a role in causing brain disorders like schizophrenia and autism where there is heightened L1 activity in the neurons of these patients. In future work, Gage and his team will study how L1s can cause changes in genes associated with schizophrenia and autism and how these changes can effect brain function and cause disease.