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

 

 

Failed stem cells may cause deadly lung disease

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Breathing is something we take for granted. It’s automatic. We don’t need to think about it. But for people with pulmonary fibrosis, breathing is something that is always on their minds.

Pulmonary fibrosis (PF) is a disease where the tissue in your lungs becomes thick and stiff, even scarred, making it difficult to breathe. It can be a frightening experience; and it doesn’t just affect your lungs.

Because your lungs don’t work properly they aren’t able to move as much oxygen as you need into your bloodstream, and that can have an impact on all your other organs, such as your brain and heart. There are some treatments but no cures, in large part because we didn’t know the cause of the disease. Many patients with PF live only 3-5 years after diagnosis.

Now a new CIRM-funded study from researchers at Cedars-Sinai has uncovered clues as to the cause of the disease, and that in turn could pave the way to new treatments.

The study, published in the journal Nature, found that a class of stem cells in the lung, called AEC2s, are responsible for helping repair damage caused by things such as pollution or infection. People who have PF have far fewer of these AEC2 cells, and those cells also had a much lower concentration of a chemical substance called hyaluronan, which is essential for repair damaged tissue.

They tested this theory with laboratory mice and found that by removing hyaluronan the mice developed thick scarring in their lungs.

In a news release from Cedars-Sinai Carol Liang, the study’s first author, said knowing the cause of the problem may help identify potential solutions:

“These findings are the first published evidence that idiopathic pulmonary fibrosis is primarily a disease of AEC2 stem cell failure. In further studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches.”

Knowing that a problem with AEC2 cells causes PF means the researchers can now start testing different medications to see which ones might help boost production of replacement AEC2 cells, or help protect those still functioning.

Stem cell agency funds clinical trials in three life-threatening conditions

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A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

As Randy Mills, our President and CEO, said in a news release:

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

First spinal cord injury trial patient gets maximum stem cell dose

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Kris Boesen, CIRM spinal cord injury clinical trial patient.

There comes a pivotal point in every experiment where you say “ok, now we are going to see if this really works.” We may be at that point in the clinical trial we are funding to see if stem cells can help people with spinal cord injuries.

Today Asterias Biotherapeutics announced they have given the first patient in the clinical trial the highest dose of 20 million cells. The therapy was administered at Santa Clara Valley Medical Center (SCVMC) in San Jose, California where Jake Javier – a young man who was treated at an earlier stage of the trial – was treated. You can read Jake’s story here.

The goal of the trial is to test the safety of transplanting three escalating doses of AST-OPC1 cells. These are a form of cell called oligodendrocyte progenitors, which are capable of becoming several different kinds of nerve cells, some of which play a supporting role and help protect nerve cells in the central nervous system – the area damaged in spinal cord injury.

In a news release, Dr. Edward Wirth, Asterias’ Chief Medical Officer, says this could be a crucial phase in the trial:

“We have been very encouraged by the early clinical efficacy and safety data for AST-OPC1, and we now look forward to evaluating the 20 million cell dose in complete cervical spinal cord injury patients. Based on extensive pre-clinical research, this is in the dosing range where we would expect to see optimal clinical improvement in these patients.”

To be eligible, individuals have to have experienced a severe neck injury in the last 30 days, one that has left them with no sensation or movement below the level of their injury, and that means they have typically lost all lower limb function and most hand and arm function.

In the first phase individuals were given 2 million cells. This was primarily to make sure that this approach was safe and wouldn’t cause any problems for the patients. The second phase boosted that dose to ten million cells. That was thought to be about half the therapeutic dose but it seemed to help all those enrolled. By 90 days after the transplant all five patients treated with ten million cells had shown some level of recovery of at least one motor level, meaning they had regained some use of their arms and/or hands on at least one side of their body. Two of the patients experienced an improvement of two motor levels. Perhaps the most impressive was Kris Boesen, who regained movement and strength in both his arms and hands. He says he is even experiencing some movement in his legs.

All this is, of course, tremendously encouraging, but we also have to sound a note of caution. Sometimes individuals experience spontaneous recovery after an accident like this. The fact that all five patients in the 10 million cell group did well suggests that this may be more than just a coincidence. That’s why this next group, the 20 million cell cohort, is so important.

As Steve McKenna, Chief of the Trauma Center at SCVMC, says; if we are truly going to see an improvement in people’s condition because of the stem cell transplant, this is when we would expect to see it:

“The early efficacy results presented in September from the 10 million cell AIS-A cohort were quite encouraging, and we’re looking forward to seeing if those meaningful functional improvements are maintained through six months and beyond. We are also looking forward to seeing the results in patients from the higher 20 million cell AST-OPC1 dose, as well as results in the first AIS-B patients.”

For more information about the Asterias clinical trial, including locations and eligibility requirements, go here: www.clinicaltrials.gov, using Identifier NCT02302157, and at the SCiStar Study Website (www.SCiStar-study.com).

We can never talk about this clinical trial without paying tribute to a tremendous patient advocate and a great champion of stem cell research, Roman Reed. He’s the driving force behind the Roman Reed Spinal Cord Injury Research Act  which helped fund the pioneering research of Dr. Hans Keirstead that laid the groundwork for this clinical trial.

 

 

Discovering stem cells and science at Discovery Day

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The CIRM booth at Discovery Day at AT&T Park

Someone stole my thigh bone. One minute it was there. The next, gone. I have narrowed down the list of suspects to the more than 25,000 people attending Discovery Day at San Francisco’s AT&T Park.

To be honest, the bone was just a laminated image of a bone, stuck to the image of a person drawn on a white board. We were using it, along with laminated images of a brain, liver, stomach and other organs and tissues, to show that there are many different kinds of stem cells in the body, and they all have different potential uses.

The white board and its body parts were gimmicks that we used to get kids to come up to the CIRM booth and ask what we were doing. Then, as they played with the images, and tried to guess which stem cells went where, we talked to their parents about stem cell research, and CIRM and the progress being made.

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Dr. Karen Ring explaining embryonic development to kids

We also used Play Doh so that the kids could model cell division and specialization during embryonic development. But mostly it was so the kids could play with the Play Doh while we talked to their parents.

It is shameless I know but when you are competing against more than 130 other booths for people’s attention – and some of these booths had live snakes, virtual reality devices, or they just let kids throw and hit things – you have to be creative.

And creativity was certainly the key word, because Discovery Day – part of the annual week-long Bay Area Science Fair – was filled with booths from companies and academic institutions promoting every imaginable aspect of science.

So why were we there? Well, first, education has been an important part of CIRM’s mission ever since we were created. Second, we’re a state agency that gets public funding so we feel we owe it to the public to explain how their money is being used. And third, it’s just a lot of fun.

NASA was there, talking about exploring deep space. And there were booths focused on exploring the oceans, and saving them from pollution and over-fishing. You could learn about mathematics and engineering by building wacky-looking paper airplanes that flew long distances, or you could just sit in the cockpit of a fighter jet.

discoveryday-victor

And everywhere you looked were families, with kids running up to the different booths to see what was there. All they needed was a little draw to get them to stick around for a few minutes, so you could talk to them and explain to them what stem cells are and why they are so amazing. Some of the kids were fascinated and wanted to know more: some just wanted to use the Play Doh;  at least one just wanted to eat the Play Doh, but fortunately we were able to stop that happening.

It was an amazing sight to see a baseball stadium filled with tens of thousands of people, all there to learn about science. At a time when we are told that kids don’t care about science, that they don’t like math, this was the perfect response. All you had to do was look around and see that kids were fascinated by science. They were hungry to learn how pouring carbon dioxide on a candle puts out the flame. They delighted in touching an otter pelt and feeling how silky smooth it is, and then looking at the pelt under a microscope to see just how extraordinarily dense the hairs are and how that helps waterproof the otter.

And so yes, we used Play Doh and a white board person to lure the kids to us. But it worked.

There was another booth where they had a couple of the San Francisco 49er’s cheerleaders in full uniform. I don’t actually know what that had to do with teaching science but it was very popular with some of the men. Maybe next year I could try dressing up like that. It would certainly draw a crowd.

Meeting the scientists who are turning their daughter’s cells into a research tool – one that could change her life forever

There’s nothing like a face-to-face meeting to really get to know someone. And when the life of someone you love is in the hands of that person, then it’s a meeting that comes packed with emotion and importance.

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Lilly Grossman

Last week Gay and Steve Grossman got to meet the people who are working with their daughter Lilly’s stem cells. Lilly was born with a rare, debilitating condition called ADCY5-related dyskinesia. It’s an abnormal involuntary movement disorder caused by a genetic mutation that results in muscle weakness and severe pain. Because it is so rare, little research has been done on developing a deeper understanding of it, and even less on developing treatments.

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The Grossmans and Chris Waters meet the Buck team

 

That’s about to change. CIRM’s Induced Pluripotent Stem Cell  iPSC Bank – at the Buck Institute for Research on Aging – is now home to some of Lilly’s cells, and these are being turned into iPS cells for researchers to study the disease, and to hopefully develop and test new drugs or other therapies.

Gay said that meeting the people who are turning Lilly’s tissue sample into a research tool was wonderful:

“I think meeting the people who are doing the actual work at the lab is so imperative, and so important. I want them to see where their work is going and how they are not only affecting our lives and our daughter’s life but also the lives of the other kids who are affected by this rare disease and all rare diseases.”

Joining them for the trip to the Buck was Chris Waters, the driving force behind getting the Bank to accept new cell lines. Chris runs Rare Science a non-profit organization that focuses on children with rare diseases by partnering with patient family communities and foundations.

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Steve and Gay Grossman and Chris Waters

In a news release, Chris says there are currently 7,000 identified rare diseases and 50 percent of those affect children; tragically 30 percent of those children die before their 5th birthday:

“The biggest gap in drug development is that we are not addressing the specific needs of children, especially those with rare diseases.  We need to focus on kids. They are our future. If it takes 14 years and $2 billion to get FDA approval for a new drug, how is that going to address the urgent need for a solution for the millions of children across the world with a rare disease? That’s why we created Rare Science. How do we help kids right now, how do we help the families? How do we make change?”

Jonathan Thomas, the Chair of the CIRM Board, said one way to help these families and drive change is by adding samples of stem cells from rare diseases like ADCY5 to the iPSC Bank:

“Just knowing the gene that causes a particular problem is only the beginning. By having the iPSCs of individuals, we can start to investigate the diseases of these kids in the labs. Deciphering the biology of why there are similarities and dissimilarities between these children could the open the door for life changing therapies.”

When CIRM launched the iPSC Initiative – working with CDI, Coriell, the Buck Institute and researchers around California – the goal was to build the largest iPSC Bank in the world.  Adding new lines, such as the cells from people with ADCY5, means the collection will be even more diverse than originally planned.

Chris hopes this action will serve as a model for other rare diseases, creating stem cell lines from them to help close the gap between discovery research and clinical impact. And she says seeing the people who are turning her idea into reality is just amazing:

“Oh my gosh. It’s just great to be here, to see all these people who are making this happen, they’re great. And I think they benefit too, by being able to put a human face on the diseases they are working on. I think you learn so much by meeting the patients and their families because they are the ones who are living with this every day. And by understanding it through their eyes, you can improve your research exponentially. It just makes so much more sense.”

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RARE Bears for RARE Science

To help raise funds for this work Rare Science is holding a special auction, starting tomorrow, of RARE Bears. These are bears that have been hand made by, and this is a real thing, “celebrity quilters”, so you know the quality is going to be amazing. All proceeds from the auction go to help RARE Science accelerate the search for treatments for the 200 million kids around the world who are undiagnosed or who have a rare disease.

 

Meat the future of stem cells. And I do mean “meat”.

'...And just a pince of stem cells.'

Over the years there have been a lot of interesting, odd ball, even a few really rather crazy stories about stem cell research that have made the news. So in honor of Halloween, we thought we’d look back at a few of them to remind ourselves that not all science is worthy of pursuit.

Celebrity meat:

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Back in 2014 a company called BiteLabs claimed it was going to make  “fine artisanal salami from meat that has been lab-grown from celebrity tissue samples.” You read that right. They were going to make salami from famous people.

Here’s how they described the process. First they would take a small sample of stem cells from the celebrity, the kind of cell that is used to grow and repair damaged muscles. Then they would grow those cells in the lab, increasing their number to millions of muscle cells. Those are then ground up, mixed with regular salami and some spices, fats and oils until you had the desired consistency and texture.

Then they were stuffed into casings, and dried, aged and cured until you end up with celebrity salami.

Not surprisingly it attracted a lot of attention. The Twitterverse was filled with images of celebrities people wanted to “eat” – Jennifer Lawrence, ‘a new kind of Hunger Games’. It was also filled with headlines from magazines like Cosmopolitan asking “Is this the weirdest food of all time”.

Turns out it was more of a joke, or at least a fun way to get people discussing bioethics and pushing the boundaries – or maybe it was the buttons – of tech and society.

Meet the most expensive meat in the world

If that was meant to be a joke then some researchers at Maastricht University in the Netherlands didn’t get it. Because the next year they actually produced a burger that was made out of stem cells.

They took some bovine – aka ‘cow’ – stem cells, grew them in the lab (this took three months so definitely not a “fast food”), then mixed them with salt, breadcrumbs and egg and cooked them in a little butter and sunflower oil.

People who tried it described it as “tough” and “not that juicy”. Harder to stomach than the burger itself was the price tag, more than $300,000.

A mammoth task

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It’s not just meat that is attracting the attention of stem cell researchers. More recently a team of Korean and Russian scientists decided it might be fun to try and use stem cells to “grow” a mammoth. You know, the giant, woolly, elephant-like creatures that went extinct thousands of years ago – except for occasional starring roles in the Ice Age animated movies.

They were going to take some DNA from the remnants of a mammoth found in the frozen tundra in Siberia, decode its genome, then create a functioning cell nucleus and transplant that into an elephant’s embryo. Easy right? What could possible go wrong (for some suggestions see Jurassic Park/World).

Maybe if that doesn’t work out they could just grow the cells into meat and market them. Mammoth burgers. Sounds yummy doesn’t it.

Happy Halloween.

 

Stem cell stories that caught our eye: How Zika may impact adult brains; Move over CRISPR there’s a new kid in town; How our bodies store fat

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

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Zika mosquito

Zika virus could impact adult brains

It’s not just a baby’s developing brain that is vulnerable to the Zika virus, adult brains may be too. A new study shows that some stem cells that help repair damage in the adult brain can be impacted by Zika. This is the first time we’ve had any indication this could be a problem in a fully developed brain.

The study, in the journal Cell Stem Cell, looked at neural progenitors, a  stem cell that plays an important role in helping replace or repair damaged neurons, or nerve cells, in the brain. The researchers exposed the cells to the Zika virus and found that it infected the cells, causing some of the cells to die, and also limited the ability of the cells to proliferate.

In an interview in Healthday, Sujan Shresta, a researcher at the La Jolla Institute for Allergy and Immunology and one of the lead authors of the study, says although their work was done in adult mice, it may have implications for people:

“Zika can clearly enter the brains of adults and can wreak havoc. But it’s a complex disease, it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle and now we know what to look for.”

Move over CRISPR, there’s a new gene-editing tool in town

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Jennifer Lopez: Photo courtesy MTV

For much of the last year the hottest topic in stem cell and gene editing research has been CRISPR and the ease with which it can be used to edit genes. It’s so hot that apparently it’s the title of an upcoming TV show starring Jeniffer Lopez.

But hold on J-Lo, a new study in Nature Communications says by the time the show is on the air it may be old hat. Researchers at Carnegie Mellon and Yale University have developed a new gene-editing system, one they claim is easier to use and more accurate than CRISPR. And to prove it, they say they have successfully cured a genetic blood disorder in mice, using a simple IV approach.

Tools like CRISPR use enzymes to cut open sections of DNA to edit a specific gene. It’s like using a pair of scissors to cut a piece of string that has a big knot in the middle; you cut out the knot then join the ends of the string together. The problem with CRISPR is that the enzymes it uses are quite large and hard to use in a living animal – let alone a human – so they have to remove the target cells from the body and do the editing in the lab. Another problem is that CRISPR sometimes cuts sections of DNA that the researchers don’t want cut and could lead to dangerous side effects.

Greater precision

The Carnegie Mellon/Yale team say their new method avoids both problems. They use nanoparticles that contain molecules made from peptide nucleic acid (PNA), a kind of artificial form of DNA. This PNA is engineered to be able to cut open DNA and bind to a specific target without cutting anything else.

The team used this approach to target the mutated gene in beta thalassemia, a blood disorder that can be fatal if left untreated. The therapy binds to the malfunctioning gene, enabling the body’s own DNA repair system to correct the problem.

In a news story in Science Daily Danith Ly, one of the lead authors on the study, says even though the technique was successful in editing the target genes just 7 percent of the time, that is way more than the 0.1 percent rate most other gene editing tools achieve.

“The effect may only be 7 percent, but that’s curative. In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100 percent to see the phenotype return to normal.”

Hormone that controls if and when fat cells mature

Obesity is one of the fastest growing public health problems in the US and globally. Understanding the mechanisms behind how that happens could be key to finding ways to address it. Now researchers at Stanford University think they may have uncovered an important part of the answer.

Their findings, reported in Science Signaling, show that mature fat cells produce a hormone called Adamts1 which acts like a switch for surrounding stem cells, determining if they change into fat-storing cells.   People who eat a high-fat diet experience a change in their Adamst1 production, and that triggers the nearby stem cells to specialize and start storing fat.

There are still a lot of questions to be answered about Adamst1, including whether it acts alone or in conjunction with other as yet unknown hormones. But in an article in Health Canal, Brian Feldman, the senior author of the study, says they can now start looking at potential use of Adamst1 to fight obesity.

“That won’t be a simple answer. If you block fat formation, extra calories have to go somewhere in the body, and sending them somewhere else outside fat cells could be more detrimental to metabolism. We know from other researchers’ work that liver and muscle are both bad places to store fat, for example. We do think there are going to be opportunities for new treatments based on our discoveries, but not by simply blocking fat formation alone.”

 

Ingenious CIRM-funded stem cell approach to treating ALS gets go-ahead to start clinical trial

svend

Clive Svendsen

Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, was first identified way back in 1869 but today, more than 150 years later, there are still no effective treatments for it. Now a project, funded by CIRM, has been given approval by the Food and Drug Administration (FDA) to start a clinical trial that could help change that.

Clive Svendsen and his team at Cedars-Sinai are about to start a clinical trial they hope will help slow down the progression of the disease. And they are doing it in a particularly ingenious way. More on that in a minute.

First, let’s start with ALS itself. It’s a particularly nasty, rapidly progressing disease that destroys motor neurons, those are the nerve cells in the brain and spinal cord that control movement. People with ALS lose the ability to speak, eat, move and finally, breathe. The average life expectancy after diagnosis is just 3 – 4 years. It’s considered an orphan disease because it affects only around 30,000 people in the US; but even with those relatively low numbers that means that every 90 minutes someone in the US is diagnosed with ALS, and every 90 minutes someone in the US dies of ALS.

Ingenious approach

In this clinical trial the patients will serve as their own control group. Previous studies have shown that the rate of deterioration of muscle movement in the legs of a person with ALS is the same for both legs. So Svendsen and his team will inject specially engineered stem cells into a portion of the spine that controls movement on just one side of the body. Neither the patient nor the physician will know which side has received the cells. This enables the researchers to determine if the treated leg is deteriorating at a slower rate than the untreated leg.

The stem cells being injected have been engineered to produce a protein called glial cell line derived neurotrophic factor (GDNF) that helps protect motor neurons. Svendsen and the team hope that by providing extra GDNF they’ll be able to protect the motor neurons and keep them alive.

Reaching a milestone

In a news release announcing the start of the trial, Svendsen admitted ALS is a tough disease to tackle:

“Any time you’re trying to treat an incurable disease, it is a long shot, but we believe the rationale behind our new approach is strong.”

Diane Winokur, the CIRM Board patient advocate for ALS, says this is truly a milestone:

“In the last few years, thanks to new technologies, increased interest, and CIRM support, we finally seem to be seeing some encouraging signs in the research into ALS. Dr. Svendsen has been at the forefront of this effort for the 20 years I have followed his work.  I commend him, Cedars-Sinai, and CIRM.  On behalf of those who have suffered through this cruel disease and their families and caregivers, I am filled with hope.”

You can read more about Clive Svendsen’s long journey to this moment here.

 

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

hitting-machine

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.