CIRM-funded life-saving stem cell therapy gets nod of approval from FDA

Cured_AR_2016_coverIf you have read our 2016 Annual Report (and if you haven’t you should, it’s brilliant) or just seen the cover you’ll know that it features very prominently a young girl named Evie Padilla Vaccaro.

Evie was born with Severe Combined Immunodeficiency or SCID – also known as “bubble baby disease”; we’ve written about it here. SCID is a rare but deadly immune disorder which leaves children unable to fight off simple infections. Many children with SCID die in the first few years of life.

Fortunately for Evie and her family, Dr. Don Kohn and his team at UCLA, working with a UK-based company called Orchard Therapeutics Ltd., have developed a treatment called OTL-101. This involves taking the patient’s own blood stem cells, genetically modifying them to correct the SCID mutation, and then returning the cells to the patient. Those modified cells create a new blood supply, and repair the child’s immune system.

Evie was treated with OTL-101 when she was a few months old. She is cured. And she isn’t the only one. To date more than 40 children have been treated with this method. All have survived and are doing well.

Orchard Therapeutics

 FDA acknowledgement

Because of that success the US Food and Drug Administration (FDA) has granted OTL-101 Rare Pediatric Disease Designation. This status is given to a treatment that targets a serious or life-threatening disease that affects less than 200,000 people, most of whom are under 18 years of age.

The importance of the Rare Pediatric Disease Designation is that it gives the company certain incentives for the therapy’s development, including priority review by the FDA. That means if it continues to show it is safe and effective it may have a faster route to being made more widely available to children in need.

In a news release Anne Dupraz, PhD, Orchard’s Chief Regulatory Officer, welcomed the decision:

“Together with Orphan Drug and Breakthrough Therapy Designations, this additional designation is another important development step for the OTL-101 clinical program. It reflects the potential of this gene therapy treatment to address the significant unmet medical need of children with ADA-SCID and eligibility for a Pediatric Disease Priority Review voucher at time of approval.”

Creating a trend

This is the second time in less than two weeks that a CIRM-funded therapy has been awarded Rare Pediatric Disease designation. Earlier this month Capricor Therapeutics was given that status for its treatment for Duchenne Muscular Dystrophy.

Two other CIRM-funded clinical trials – Humacyte and jCyte – have been given Regenerative Medicine Advanced Therapy Designation (RMAT) by the FDA. This makes them eligible for earlier and faster interactions with the FDA, and also means they may be able to apply for priority review and faster approval.

All these are encouraging signs for a couple of reasons. It suggests that the therapies are showing real promise in clinical trials. And it shows that the FDA is taking steps to encourage those therapies to advance as quickly – and safely of course – as possible.

Credit where credit is due

In the past we have been actively critical of the FDA’s sluggish pace in moving stem cell therapies out of the lab and into clinical trials where they can be tested in people. So when the FDA does show signs of changing the way it works it’s appropriate that that we are actively supportive.

Getting these designations is, of course, no guarantee the therapies will ultimately prove to be successful. But if they are, creating faster pathways means they can get to patients, the people who really need them, at a much faster pace.

 

 

 

 

 

World Sickle Cell Day: A View from the Front Line

June 19th is World Sickle Cell Day. Sickle cell disease is an inherited blood disorder that causes normally round red blood cells to take on an abnormal sickle shape, resulting in clogged arteries, severe pain, increased risk of stroke and reduced life expectancy. To mark the occasion we asked Nancy M. Rene to write a guest blog for us. Nancy is certainly qualified; she is the grandmother of a child with sickle cell disease, and the co-founder of Axis Advocacy, a non-profit advocating for those with sickle cell disease and their families.

Nancy ReneOn this World Sickle Cell Day, 2017, we can look back to the trailblazers in the fight against Sickle Cell Disease.  More than 40 years ago, the Black Panther Party established the People’s Free Medical Clinics in several cities across the country. One of the functions of these free clinics: to screen people for sickle cell disease and sickle cell trait. This life-saving screening began  in 1971.

Around that same time, President Richard Nixon allocated $10 million to begin the National Sickle Cell Anemia Control Act. This included counseling and screening, educational activities, and money for research.

In the early part of the twentieth century, most children with sickle cell died before their fifth birthday. With newborn screening available nationwide, the use of penicillin to prevent common infections, and the finding that hydroxyurea was useful in fighting the disease, life expectancy began to improve.

For much of the twentieth century, people with sickle cell disease felt that they were fighting the fight alone, knowledgeable doctors were scarce and insurance was often denied.

Making progress

As we moved into the twenty-first century, patients and families found they had some powerful allies. The National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) joined the battle.  In 2016 the NIH held its tenth annual international conference on sickle cell disease that featured speakers from all over the world.  Participants were able to learn about best practices in Europe, Africa, India, and South America.

Sickle Cell centers at Howard University, the Foundation for Sickle Cell Disease Research, and other major universities across the country are pointing the way to the best that medicine has to offer.

Last year, the prestigious American Society of Hematology (ASH) launched an initiative to improve understanding and treatment of sickle cell disease.  Their four-point plan includes education, training, advocacy, and expanding its global reach.

Just last month, May 2017, the FDA looked at Endari, developed by Emmaus Medical in Torrance, California.  It is the first drug specifically developed for sickle cell disease to go through the FDA’s approval process. We should have a decision on whether or not the drug goes to market in July.

The progress that had been made up to the beginning of the twenty-first century was basically about alleviating the symptoms of the disease: the sickling, the organ damage and the pervasive anemia. But a cure was still elusive.

But in 2004, California’s Stem Cell Agency, CIRM, was created and it was as if the gates had opened.

Researchers had a new source of funding to enable  them to work on Sickle Cell Disease and many other chronic debilitating diseases at the cellular level. Scientists like Donald Kohn at UCLA, were able to research gene editing and find ways to use autologous bone marrow transplants to actually cure people with sickle cell. While some children with sickle cell have been cured with traditional bone marrow transplants, these transplants must come from a matched donor, and for most patients, a matched donor is simply not available. CIRM has provided the support needed so that researchers are closing in on the cure. They are able to share strategies with doctors and researchers throughout the world

And finally, support from the federal government came with the passage of the Affordable Care Act and adequate funding for the NIH, CDC, the Health Resources and Services Administration (HRSA), and FDA.

Going backwards

And yet, here we are, World Sickle Cell Day, 2017.

Will this be a case of one step forward two steps back?

Are we really going back to the time when people with Sickle Cell Disease could not get health insurance because sickle cell is a pre-existing condition, to the time when there was little money and no interest in research or professional training, to a time when patients and their families were fighting this fight alone?

For all of those with chronic disease, it’s as if we are living a very bad dream.

Time to wake up

For me, I want to wake up from that dream.  I want to look forward to a future where patients and families, where Joseph and Tiffany and Marissa and Ken and Marcus and all the others, will no longer have to worry about getting well-informed, professional treatment for their disease.

Where patients will no longer fear going to the Emergency Room

Where doctors and researchers have the funding they need to support them in their work toward the cure,

Where all children, those here in the United States along with those in Africa, India, and South America, will have access to treatments that can free them from pain and organ damage of sickle cell disease.

And where all people with this disease can be cured.

Latest space launch sends mice to test bone-building drug

Illustration of mice adapting to their custom-designed space habitat on board the International Space Station. Image courtesy of the Center for the Advancement of Science in Space

Astronauts on the International Space Station (ISS) received some furry guests this weekend with the launch of SpaceX’s Dragon supply capsule. On Saturday June 3rd, 40 mice were sent to the ISS along with other research experiments and medical equipment. Scientists will be treating the mice with a bone-building drug in search of a new therapy to combat osteoporosis, a disease that weakens bones and affects over 200 million people globally.

The bone-building therapy comes out of CIRM-funded research by UCLA scientists Dr. Chia Soo, Dr. Kang Ting and Dr. Ben Wu. Back in 2015, the UCLA team published that a protein called NELL-1 stimulates bone-forming stem cells, known as mesenchymal stem cells, to generate new bone tissue more efficiently in mice. They also found that NELL-1 blocked the function of osteoclasts – cellular recycling machines that break down and absorb bone – thus increasing bone density in mice.

Encouraged by their pre-clinical studies, the team decided to take their experiments into space. In collaboration with NASA and a grant from the Center for the Advancement of Science in Space (CASIS), they made plans to test NELL-1’s effects on bone density in an environment where bone loss is rapidly accelerated due to microgravity conditions.

Bone loss is a major concern for astronauts living in space for extended periods of time. The earth’s gravity puts pressure on our bones, stimulating bone-forming cells called osteoblasts to create new bone. Without gravity, osteoblasts stop functioning while the rate of bone resorption increases by approximately 1.5% per month. This translates to almost a 10% loss in bone density for every 6 months in space.

In a UCLA news release, Dr. Wu explained how they modified the NELL-1 treatment to stand up to the tests of space:

“To prepare for the space project and eventual clinical use, we chemically modified NELL-1 to stay active longer. We also engineered the NELL-1 protein with a special molecule that binds to bone, so the molecule directs NELL-1 to its correct target, similar to how a homing device directs a missile.”

The 40 mice will receive NELL-1 injections for four weeks on the ISS, at which point, half of the mice will be sent back to earth to receive another four weeks of NELL-1 treatment. The other half will stay in space and receive the same treatment so the scientists can compare the effects of NELL-1 in space and on land.

The Rodent Research Hardware System includes three modules: Habitat, Transporter, and Animal Access Unit.
Credits: NASA/Dominic Hart

The UCLA researchers hope that NELL-1 will prevent bone loss in the space mice and could lead to a new treatment for bone loss or bone injury in humans. Dr. Soo explained in an interview with SpaceFlight Now,

“We are hoping this study will give us some insights on how NELL-1 can work under these extreme conditions and if it can work for treating microgravity-related bone loss, which is a very accelerated, severe form of bone loss, then perhaps it can (be used) for patients one day on Earth who have bone loss due to trauma or due to aging or disease.”

If you want to learn more about this study, watch this short video below provided by UCLA. 

Stem cell stories that caught our eye: better ovarian cancer drugs, creating inner ear tissue, small fish big splash

Two drugs are better than one for ovarian cancer (Karen Ring). Earlier this week, scientists from UCLA reported that a combination drug therapy could be an effective treatment for 50% of aggressive ovarian cancers. The study was published in the journal Precision Oncology and was led by Dr. Sanaz Memarzadeh.

Women with high-grade ovarian tumors have an 85% chance of tumor recurrence after treatment with a common chemotherapy drug called carboplatin. The UCLA team found in a previous study that ovarian cancer stem cells are to blame because they are resistant to carboplatin. It’s because these stem cells have an abundance of proteins called cIAPs, which prevent cell death from chemotherapy.

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Ovarian cancer cells (blue) expressing cIAP protein (red) on the left are more sensitive to a combination therapy than cancer cells that don’t express the protein on the right. (UCLA Broad Stem Cell Research Center/Precision Oncology)

Memarzadeh discovered that an experimental drug called birinapant made some ovarian cancer tumors more sensitive to chemotherapy treatment by breaking down cIAPs. This gave her the idea that combining the two drugs, birinapant and carboplatin, might be a more effective strategy for treating aggressive ovarian tumors.

By treating with the two drugs simultaneously, the scientists improved the survival rate of mice with ovarian cancer. They also tested this combo drug treatment on 23 ovarian cancer cell lines derived from women with highly aggressive tumors. The treatment killed off half of the cell lines indicating that some forms of this cancer are resistant to the combination treatment.

When they measured the levels of cIAPs in the human ovarian cancer cell lines, they found that high levels of the proteins were associated with ovarian tumor cells that responded well to the combination treatment. This is exciting because it means that clinicians can analyze tumor biopsies for cIAP levels to determine whether certain ovarian tumors would respond well to combination therapy.

Memarzadeh shared her plans for future research in a UCLA news release,

“I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy.”

In a first, researchers create inner ear tissue. From heart muscle to brain cells to insulin-producing cells, researchers have figured out how to make a long list of different human cell types using induced pluripotent stem cells (iPSCs) – cells taken from the body and reprogrammed into a stem cell-like state.

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Human inner ear organoid with sensory hair cells (cyan) and sensory neurons (yellow). An antibody for the protein CTBP2 reveals cell nuclei as well as synapses between hair cells and neurons (magenta). | Photo: Karl Koehler

This week, a research group at the Indiana University School of Medicine successfully added inner ear cells to that list. This feat, published in Nature Biotechnology, is especially important given the fact that the inner ear is one of the few parts of the body that cannot be biopsied for further examination. With these cells in hands, new insights into the causes of hearing loss and balance disorders may be on the horizon.

The inner ear contains 75,000 sensory hair cells that convert sound waves into electrical signals to the brain. Loud noises, drug toxicity, and genetic mutations can permanently damage the hair cells leading to hearing loss and dizziness. Over 15%  of the U.S. population have some form of hearing loss and that number swells to 67% for people over 75.

Due to the complex shape of the inner ear, the team grew the iPSCs into three dimensional balls of cells rather than growing them as a flat layer of cells on a petri dish. With educated guesses sprinkled in with some trial and error, the scientists, for the time, identified a recipe of proteins that stimulated the iPSCs to transform into inner ear tissue. And like any great recipe, it wasn’t so much the ingredient list but the timing that was key:

“If you apply these signals at the wrong time you can potentially generate a brain instead of an inner ear,” first author Dr. Karl Koehler said in an interview with Gizmodo. “The real breakthrough is that we figured out the exact timing to do each one of these [protein] treatments.”

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Senior author, Eri Hashino, Ph.D., and first author, Karl R. Koehler, Ph.D. Photo: Indiana University

Careful examination shows that the tissue, referred to as organoids, not only contained the sensory hair cells of the inner ear cell but also nerve cells, or neurons, that are responsible for relaying the sound waves to the brain. Koehler explained the importance of this result in a press release:

“We also found neurons, like those that transmit signals from the ear to the brain, forming connections with sensory cells. This is an exciting feature of these organoids because both cell types are critical for proper hearing and balance.”

Though it’s still early days, these iPSC-derived inner ear organoids are a key step toward the ultimate goal of repairing hearing loss. Senior author, Dr. Eri Hashino, talked about the team’s approach to reach that goal:

“Up until now, potential drugs or therapies have been tested on animal cells, which often behave differently from human cells. We hope to discover new drugs capable of helping regenerate the sound-sending hair cells in the inner ear of those who have severe hearing problems.”

This man’s research is no fish tale
And finally, we leave you this week with a cool article and video by STAT. It features Dr. Leonard Zon of Harvard University and his many, many tanks full of zebrafish. This little fish has made a huge splash in understanding human development and disease. But don’t take my word for it, watch the video!

Stem cell stories that caught our eye: developing the nervous system, aging stem cells and identical twins not so identical

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

New theory for how the nervous system develops.

There’s a new theory on the block for how the nervous system is formed thanks to a study published yesterday by UCLA stem cell scientists in the journal Neuron.

The theory centers around axons, thin extensions projecting from nerve cells that transmit electrical signals to other cells in the body. In the developing nervous system, nerve cells extend axons into the brain and spinal cord and into our muscles (a process called innervation). Axons are guided to their final destinations by different chemicals that tell axons when to grow, when to not grow, and where to go.

Previously, scientists believed that one of these important chemical signals, a protein called netrin 1, exerted its influence over long distances in a gradient-like fashion from a structure in the developing nervous system called the floor plate. You can think of it like a like a cell phone tower where the signal is strongest the closer you are to the tower but you can still get some signal even when you’re miles away.

The UCLA team, led by senior author and UCLA professor Dr. Samantha Butler, questioned this theory because they knew that neural progenitor cells, which are the precursors to nerve cells, produce netrin1 in the developing spinal cord. They believed that the netrin1 secreted from these progenitor cells also played a role in guiding axon growth in a localized manner.

To test their hypothesis, they studied neural progenitor cells in the developing spines of mouse embryos. When they eliminated netrin1 from the neural progenitor cells, the axons went haywire and there was no rhyme or reason to their growth patterns.

Left: axons (green, pink, blue) form organized patterns in the normal developing mouse spinal cord. Right: removing netrin1 results in highly disorganized axon growth. (UCLA Broad Stem Cell Research Center/Neuron)

A UCLA press release explained what the scientists discovered next,

“They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system.”

Like how ants leave chemical trails for other ants in their colony to follow, neural progenitor cells leave trails of netrin1 in the spinal cord to direct where axons go. The UCLA team believes they can leverage this newfound knowledge about netrin1 to make more effective treatments for patients with nerve damage or severed nerves.

In future studies, the team will tease apart the finer details of how netrin1 impacts axon growth and how it can be potentially translated into the clinic as a new therapeutic for patients. And from the sounds of it, they already have an idea in mind:

“One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Coating such nerve channels with netrin1 could further encourage axon regrowth.”

Age could be written in our stem cells.

The Harvard Gazette is running an interesting series on how Harvard scientists are tackling issues of aging with research. This week, their story focused on stem cells and how they’re partly to blame for aging in humans.

Stem cells are well known for their regenerative properties. Adult stem cells can rejuvenate tissues and organs as we age and in response to damage or injury. However, like most house hold appliances, adult stem cells lose their regenerative abilities or effectiveness over time.

Dr. David Scadden, co-director of the Harvard Stem Cell Institute, explained,

“We do think that stem cells are a key player in at least some of the manifestations of age. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.”

Harvard scientists have evidence suggesting that certain tissues, such as nerve cells in the brain, age sooner than others, and they trigger other tissues to start the aging process in a domino-like effect. Instead of treating each tissue individually, the scientists believe that targeting these early-onset tissues and the stem cells within them is a better anti-aging strategy.

David Sadden, co-director of the Harvard Stem Cell Institute.
(Jon Chase/Harvard Staff Photographer)

Dr. Scadden is particularly interested in studying adult stem cell populations in aging tissues and has found that “instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.”

If you lose the stem cell that’s the best at regenerating, that tissue might age more rapidly.  Dr. Scadden compares it to a game of chess, “If we’re graced and happen to have a queen and couple of bishops, we’re doing OK. But if we are left with pawns, we may lose resilience as we age.”

The Harvard Gazette piece also touches on a changing mindset around the potential of stem cells. When stem cell research took off two decades ago, scientists believed stem cells would grow replacement organs. But those days are still far off. In the immediate future, the potential of stem cells seems to be in disease modeling and drug screening.

“Much of stem cell medicine is ultimately going to be ‘medicine,’” Scadden said. “Even here, we thought stem cells would provide mostly replacement parts.  I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

I encourage you to read the full feature as I only mentioned a few of the highlights. It’s a nice overview of the current state of aging research and how stem cells play an important role in understanding the biology of aging and in developing treatments for diseases of aging.

Identical twins not so identical (Todd Dubnicoff)

Ever since Takahashi and Yamanaka showed that adult cells could be reprogrammed into an embryonic stem cell-like state, researchers have been wrestling with a key question: exactly how alike are these induced pluripotent stem cells (iPSCs) to embryonic stem cells (ESCs)?

It’s an important question to settle because iPSCs have several advantages over ESCs. Unlike ESCs, iPSCs don’t require the destruction of an embryo so they’re mostly free from ethical concerns. And because they can be derived from a patient’s cells, if iPSC-derived cell therapies were given back to the same patient, they should be less likely to cause immune rejection. Despite these advantages, the fact that iPSCs are artificially generated by the forced activation of specific genes create lingering concerns that for treatments in humans, delivering iPSC-derived therapies may not be as safe as their ESC counterparts.

Careful comparisons of DNA between iPSCs and ESCs have shown that they are indeed differences in chemical tags found on specific spots on the cell’s DNA. These tags, called epigenetic (“epi”, meaning “in addition”) modifications can affect the activity of genes independent of the underlying genetic sequence. These variations in epigenetic tags also show up when you compare two different preparations, or cell lines, of iPSCs. So, it’s been difficult for researchers to tease out the source of these differences. Are these differences due to the small variations in DNA sequence that are naturally seen from one cell line to the other? Or is there some non-genetic reason for the differences in the iPSCs’ epigenetic modifications?

Marian and Vivian Brown, were San Francisco’s most famous identical twins. Photo: Christopher Michel

A recent CIRM-funded study by a Salk Institute team took a clever approach to tackle this question. They compared epigenetic modifications between iPSCs derived from three sets of identical twins. They still found several epigenetic variations between each set of twins. And since the twins have identical DNA sequences, the researchers could conclude that not all differences seen between iPSC cell lines are due to genetics. Athanasia Panopoulos, a co-first author on the Cell Stem Cell article, summed up the results in a press release:

“In the past, researchers had found lots of sites with variations in methylation status [specific term for the epigenetic tag], but it was hard to figure out which of those sites had variation due to genetics. Here, we could focus more specifically on the sites we know have nothing to do with genetics. The twins enabled us to ask questions we couldn’t ask before. You’re able to see what happens when you reprogram cells with identical genomes but divergent epigenomes, and figure out what is happening because of genetics, and what is happening due to other mechanisms.”

With these new insights in hand, the researchers will have a better handle on interpreting differences between individual iPSC cell lines as well as their differences with ESC cell lines. This knowledge will be important for understanding how these variations may affect the development of future iPSC-based cell therapies.

A life-threatening childhood disease and the CIRM-funded team seeking a stem cell cure featured in new video

“My hope for Brooke is she can one day look back and we have to remind her of the disease she once had.”

That’s Clay Emerson’s biggest hope for his young daughter Brooke, who has cystinosis, a life-threatening genetic disease that appears by the age of two and over time causes damage to many organs, especially the kidneys and eyes but also the liver, muscle, brain, pancreas and other tissues. The Emersons and other families affected by the disease are featured in a recent video produced by the Cystinosis Research Foundation.

I doubt many can watch the seven-minute piece without getting a lump in their throat or watery eyes. One of many heart wrenching scene shows Brooke’s mother, Jill Emerson, preparing a day’s worth of medicine that she administers through a tube connected to Brook’s stomach.

“Brooke takes about 20 doses of medication a day and that’s throughout the 24hr period in a day. The poor kid hasn’t had a full night’s sleep ever in her entire life because I have to wake her up to take her life-saving medicine.”

Jill Emerson prepares a day’s worth of medicine for her daughter Brooke. Unfortunately, the treatments only slow the progression of cystinosis but don’t cure it. (Video Still: Cystinosis Research Foundation)

But these treatments only slow down the progression of this incurable disease. Even perfect compliance with taking the medicine doesn’t stop severe complications of the disease including kidney failure, diabetes, muscle weakness, and difficulty swallowing just to name a few. Cystinosis also shorten life spans. Natalie, the video’s narrator, a young woman with cystinosis wonders how much time she has left:

“There are people in their 20s who have recently died from cystinosis. I am 25 years old and I often think about how long I have to live. I’m praying for a cure for all of us.”

Her prayers may be answered in the form of a stem cell gene therapy treatment. UCSD researcher Dr. Stephanie Cherqui, who is also featured in the video, received $5 million in CIRM funding to bring her team’s therapy to clinical trials in people.

At a cellular level, cystinosis is caused by mutations in a gene called CTNS which lead to an accumulation of the amino acid cysteine. The excess cysteine eventually forms crystals causing devastating damage to cells throughout the body. Cherqui’s treatment strategy is to take blood stem cells from affected individuals, insert a good copy of the CTNS gene using genome editing into the cells’ DNA, and then transplant the cells back into the patient.

Cystinosis_Cherqui

Dr. Stephanie Cherqui and her team are working hard to bring a stem cell gene therapy treatment for cystinosis to clinical trials. (Video Still: Cystinosis Research Foundation)

Her team has preliminary evidence that the strategy works in mice. Now, they will use the CIRM grant to complete these pre-clinical studies and prepare the genetically engineered blood stem cells for use in patients. These steps are necessary to get the green light from the Food and Drug Administration (FDA) to begin clinical trials, hopefully some time this year.

Cherqui says that if all goes well, the treatment approach may have benefits beyond cystinosis:

“If we can bring this to the finish line, we can then show the way to maybe hundreds, maybe thousands of other genetic diseases. So this could be a real benefit to mankind.”

Bye Bye bubble baby disease: promising results from stem cell gene therapy trial for SCID

Evangelina Padilla-Vaccaro
(Front cover of CIRM’s 2016 Annual Report)

You don’t need to analyze any data to know for yourself that Evangelina Vaccaro’s experimental stem cell therapy has cured her of a devastating, often fatal disease of the immune system. All you have to do is look at a photo or video of her to see that she’s now a happy, healthy 5-year-old with a full life ahead of her.

But a casual evaluation of one patient won’t get therapies approved in the U.S. by the Food and Drug Administration (FDA). Instead, a very careful collection of quantitative data from a series of clinical trial studies is a must to prove that a treatment is safe and effective. Each study’s results also provide valuable information on how to tweak the procedures to improve each follow on clinical trial.

A CIRM-funded clinical trial study published this week by a UCLA research team in the Journal of Clinical Investigation did just that. Of the ten participants in the trial, nine including Evangelina were cured of adenosine deaminase-deficient severe combined immunodeficiency, or ADA-SCID, a disease that is usually fatal within the first year of life if left untreated.

In the past, children with SCID were isolated in a germ-free sterile clear plastic bubbles, thus the name “bubble baby disease”. [Credit: Baylor College of Medicine Archives]

ADA-SCID, also referred to as bubble baby disease, is so lethal because it destroys the ability to fight off disease. Affected children have a mutation in the adenosine deaminase gene which, in early development, causes the death of cells that normally would give rise to the immune system. Without those cells, ADA-SCID babies are born without an effective immune system. Even the common cold can be fatal so they must be sheltered in clean environments with limited physical contact with family and friends and certainly no outdoor play.

A few treatments exist but they have limitations. The go-to treatment is a blood stem cell transplant (also known as a bone marrow transplant) from a sibling with matched blood. The problem is that a match isn’t always available and a less than perfect match can lead to serious, life-threatening complications. Another treatment called enzyme replacement therapy (ERT) involves a twice-weekly injection of the missing adenosine deaminase enzyme. This approach is not only expensive but its effectiveness in restoring the immune system varies over a lifetime.

Evangelina being treated by Don Kohn and his team in 2012.  Photo: UCLA

The current study led by Don Kohn, avoids donor cells and enzyme therapy altogether by fixing the mutation in the patient’s own cells. Blood stem cells are isolated from a bone marrow sample and taken back to the lab where a functional copy of the adenosine deaminase gene is inserted into the patient’s cells. When those cells are ready, the patient is subjected to drugs – the same type that are used in cancer therapy – that kill off a portion of the patient’s faulty immune system to provide space in the bone marrow. Then the repaired blood stem cells are transplanted back into the body where they settle into the bone marrow and give rise to a healthy new immune system.

The ten patients were treated between 2009 and 2012 and their health was followed up for at least four years. As of June 2016, nine of the patients in the trial – (all infants except for an eight-year old) – no longer need enzyme injections and have working immune systems that allow them to play outside, attend school and survive colds and other infections that inevitably get passed around the classroom. The tenth patient was fifteen years old at the time of the trial and their treatment was not effective suggesting that early intervention is important. No serious side effects were seen in any of the patients.

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Evangelina Vaccaro (far right), who received Dr. Kohn’s treatment for bubble baby disease in 2012, with her family before her first day of school. Photo: UCLA, courtesy of the Vaccaro family

Now, this isn’t the first ever stem cell gene therapy clinical trial to successfully treat ADA-SCID. Kohn’s team and others have carried out clinical trials over the past few decades, and this current study builds upon the insights of those previous results. In a 2014 press release reporting preliminary results of this week’s published journal article, Kohn described the importance of these follow-on clinical trials for ensuring the therapy’s success:

UCLA Jonsson Comprehensive Cancer Center
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Don Kohn

“We were very happy that over the course of several clinical trials and after making refinements and improvements to the treatment protocol, we are now able to provide a cure for babies with this devastating disease using the child’s own cells.”

The team’s next step is getting FDA approval to use this treatment in all children with ADA-SCID. To reach this aim, the team is carrying out another clinical trial which will test a frozen preparation of the repaired blood stem cells. Being able to freeze the therapy product buys researchers more time to do a thorough set of safety tests on the cells before transplanting them into the patient. A frozen product is also much easier to transport for treating children who live far from the laboratories that perform the gene therapy. In November of last year, CIRM’s governing Board awarded Kohn’s team $20 million to support this project.

If everything goes as planned, this treatment will be the first stem cell gene therapy ever approved in the U.S. We look forward to adding many new photos next to Evangelina’s as more and more children are cured of ADA-SCID.

Stem Cell Stories that Caught our Eye: stem cell insights into anorexia, Zika infection and bubble baby disease

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.

Stem cell model identifies new culprit for anorexia.

Eating disorders like anorexia nervosa are often thought to be caused by psychological disturbances or societal pressure. However, research into the genes of anorexia patients suggests that what’s written in your DNA can be associated with an increased vulnerability to having this disorder. But identifying individual genes at fault for a disease this complex has remained mostly out of scientists’ reach, until now.

A CIRM-funded team from the UC San Diego (UCSD) School of Medicine reported this week that they’ve developed a stem cell-based model of anorexia and used it to identify a gene called TACR1, which they believe is associated with an increased likelihood of getting anorexia.

They took skin samples from female patients with anorexia and reprogrammed them into induced pluripotent stem cells (iPSCs). These stem cells contained the genetic information potentially responsible for causing their anorexia. The team matured these iPSCs into brain cells, called neurons, in a dish, and then studied what genes got activated. When they looked at the genes activated by anorexia neurons, they found that TACR1, a gene associated with psychiatric disorders, was switched on higher in anorexia neurons than in healthy neurons. These findings suggest that the TACR1 gene could be an identifier for this disease and a potential target for developing new treatments.

In a UCSD press release, Professor and author on the study, Alysson Muotri, said that they will follow up on their findings by studying stem cell lines derived from a larger group of patients.

Alysson Muotri UC San Diego

“But more to the point, this work helps make that possible. It’s a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of anorexia nervosa — and perhaps our ability to create new therapies.”

Anorexia is a disease that affects 1% of the global population and although therapy can be an effective treatment for some, many do not make a full recovery. Stem cell-based models could prove to be a new method for unlocking new clues into what causes anorexia and what can cure it.

Nature versus Zika, who will win?

Zika virus is no longer dominating the news headlines these days compared to 2015 when large outbreaks of the virus in the Southern hemisphere came to a head. However, the threat of Zika-induced birth defects, like microcephaly to pregnant women and their unborn children is no less real or serious two years later. There are still no effective vaccines or antiviral drugs that prevent Zika infection but scientists are working fast to meet this unmet need.

Speaking of which, scientists at UCLA think they might have a new weapon in the war against Zika. Back in 2013, they reported that a natural compound in the body called 25HC was effective at attacking viruses and prevented human cells from being infected by viruses like HIV, Ebola and Hepatitis C.

When the Zika outbreak hit, they thought that this compound could potentially be effective at preventing Zika infection as well. In their new study published in the journal Immunity, they tested a synthetic version of 25HC in animal and primate models, they found that it protected against infection. They also tested the compound on human brain organoids, or mini brains in a dish made from pluripotent stem cells. Brain organoids are typically susceptible to Zika infection, which causes substantial cell damage, but this was prevented by treatment with 25HC.

Left to right: (1) Zika virus (green) infects and destroys the formation of neurons (pink) in human stem cell-derived brain organoids.  (2) 25HC blocks Zika infection and preserves neuron formation in the organoids. (3) Reduced brain size and structure in a Zika-infected mouse brain. (4) 25HC preserves mouse brain size and structure. Image courtesy of UCLA Stem Cell.

A UCLA news release summarized the impact that this research could have on the prevention of Zika infection,

“The new research highlights the potential use of 25HC to combat Zika virus infection and prevent its devastating outcomes, such as microcephaly. The research team will further study whether 25HC can be modified to be even more effective against Zika and other mosquito-borne viruses.”

Harnessing a naturally made weapon already found in the human body to fight Zika could be an alternative strategy to preventing Zika infection.

Gene therapy in stem cells gives hope to bubble-babies.

Last week, an inspiring and touching story was reported by Erin Allday in the San Francisco Chronicle. She featured Ja’Ceon Golden, a young baby not even 6 months old, who was born into a life of isolation because he lacked a properly functioning immune system. Ja’Ceon had a rare disease called severe combined immunodeficiency (SCID), also known as bubble-baby disease.

 

Ja’Ceon Golden is treated by patient care assistant Grace Deng (center) and pediatric oncology nurse Kat Wienskowski. Photo: Santiago Mejia, The Chronicle.

Babies with SCID lack the body’s immune defenses against infectious diseases and are forced to live in a sterile environment. Without early treatment, SCID babies often die within one year due to recurring infections. Bone marrow transplantation is the most common treatment for SCID, but it’s only effective if the patient has a donor that is a perfect genetic match, which is only possible for about one out of five babies with this disease.

Advances in gene therapy are giving SCID babies like Ja’Ceon hope for safer, more effective cures. The SF Chronicle piece highlights two CIRM-funded clinical trials for SCID run by UCLA in collaboration with UCSF and St. Jude Children’s Research Hospital. In these trials, scientists isolate the bone marrow stem cells from SCID babies, correct the genetic mutation causing SCID in their stem cells, and then transplant them back into the patient to give them a healthy new immune system.

The initial results from these clinical trials are promising and support other findings that gene therapy could be an effective treatment for certain genetic diseases. CIRM’s Senior Science Officer, Sohel Talib, was quoted in the Chronicle piece saying,

“Gene therapy has been shown to work, the efficacy has been shown. And it’s safe. The confidence has come. Now we have to follow it up.”

Ja’Ceon was the first baby treated at the UCSF Benioff Children’s Hospital and so far, he is responding well to the treatment. His great aunt Dannie Hawkins said that it was initially hard for her to enroll Ja’Ceon in this trial because she was a partial genetic match and had the option of donating her own bone-marrow to help save his life. In the end, she decided that his involvement in the trial would “open the door for other kids” to receive this treatment if it worked.

Ja’Ceon Golden plays with patient care assistant Grace Deng in a sterile play area at UCSF Benioff Children’s Hospital.Photo: Santiago Mejia, The Chronicle

It’s brave patients and family members like Ja’Ceon and Dannie that make it possible for research to advance from clinical trials into effective treatments for future patients. We at CIRM are eternally grateful for their strength and the sacrifices they make to participate in these trials.

Stem Cell Stories That Caught Our Eye: Three new ways to target cancer stem cells

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.

Targeting cancer stem cells. This week, three studies came out with novel ways for targeting cancer stem cells in different types of cancers. Here’s a brief run-down of this trifecta of cancer stem cell-crushing stories:

Take your vitamins! Scientists in the UK were experimenting on cancer stem cells and comparing natural substances to on-the-market cancer drugs to determine whether any of the natural substances were effective at disrupting the metabolism (the chemical reactions that keep cells alive and functioning) of cancer stem cells. Interestingly, they found that ascorbic acid, which you’ll know as Vitamin C, was ten times better at curbing cancer stem cell growth compared to a cancer drug called 2-DG.

Vitamin C has popped up as an anti-cancer treatment in the past when Nobel Laureate Linus Pauling found that it dramatically reduced the death rate in breast cancer patients. However this current study is the first to show that Vitamin C has a direct effect on cancer stem cells.

In coverage by ScienceDaily, the UK team hinted at plans to test Vitamin C in clinical trials:

“Vitamin C is cheap, natural, non-toxic and readily available so to have it as a potential weapon in the fight against cancer would be a significant step. Our results indicate it is a promising agent for clinical trials, and a as an add-on to more conventional therapies, to prevent tumour recurrence, further disease progression and metastasis.”

 

A gene called ZEB1 determines how aggressive brain tumors are. A team from Cedars-Sinai Medical Center was interested to know how cancer stem cells in aggressive brain tumors called gliomas survive, reproduce and affect patient survival. In a study published in Scientific Reports, they studied the genetic information of over 4000 brain tumor samples and found ZEB1, a gene that regulates tumor growth and is associated with patient survival.

They found that patients with a healthy copy of the ZEB1 gene had a higher survival rate and less aggressive tumors compared to patients that didn’t have ZEB1 or had a mutated version of the gene.

In coverage by ScienceDaily, the senior author on the study explained how their study’s findings will allow for more personalized treatments for patients with glioma based on whether they have ZEB1 or not:

“Patients without the gene in their tumors have more aggressive cancers that act like stem cells by developing into an uncontrollable number of cell types. This new information could help us to measure the mutation in these patients so that we are able to provide a more accurate prognosis and treatment plan.”

 

Beating resistant tumors by squashing cancer stem cells. Our final cancer stem cell story today comes from the UCLA School of Dentistry. This team is studying another type of aggressive cancer called a squamous cell carcinoma that causes tumors in the head and neck. Often these tumors resist treatment and spread to a patient’s lymph nodes, which quickly reduces their survival rate.

The UCLA team thought that maybe pesky cancer stem cells were to blame for the aggressive and resistant nature of these head and neck tumors. In a study published in Cell Stem Cell, they developed a mouse model of head and neck carcinoma and isolated cancer stem cells from the tumors of these mice. When they studied these stem cells, they found that they expressed unique proteins compared to non-cancer cells. These included Bmi1, a well-known stem cell protein, and AP-1, a transcription factor protein that regulates other cancer genes.

At left, head and neck squamous cell carcinoma invasive growth, and at right, cancer stem cells (shown in red) in head and neck squamous cell carcinoma. (Image Demeng Chen and Cun-Yu Wang/UCLA)

After identifying the culprits, the team developed a new combination strategy that targeted the cancer stem cells while also killing off the tumors using chemotherapy drugs.

In a UCLA Newsroom press release, the lead scientist on the study Dr. Cun-Yu Wang explained the importance of their study for the future treatment of cancer and solid tumors:

“This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.”

A Clinical Trial Network Focused on Stem Cell Treatments is Expanding

Geoff Lomax is a Senior Officer of CIRM’s Strategic Initiatives.

California is one of the world-leaders in advancing stem cell research towards treatments and cures for patients with unmet medical needs. California has scientists at top universities and companies conducting cutting edge research in regenerative medicine. It also has CIRM, California’s Stem Cell Agency, which funds promising stem cell research and is advancing stem cell therapies into clinical trials. But the real clincher is that California has something that no one else has: a network of medical centers dedicated to stem cell-based clinical trials for patients. This first-of-its-kind system is called the CIRM Alpha Stem Cell Clinics Network.

Get to Know Our Alpha Clinics

In 2014, CIRM launched its Alpha Stem Cell Clinics Network to accelerate the development and delivery of stem cell treatments to patients. The network consists of three Alpha Clinic sites at UC San Diego, City of Hope in Duarte, and a joint clinic between UC Los Angeles and UC Irvine. Less than three years since its inception, the Alpha Clinics are conducting 34 stem cell clinical trials for a diverse range of diseases such as cancer, heart disease and sickle cell anemia. You can find a complete list of these clinical trials on our Alpha Clinics website. Below is an informational video about our Alpha Clinics Network.

So far, hundreds of patients have been treated at our Alpha Clinics. These top-notch medical centers use CIRM-funding to build teams specialized in overseeing stem cell trials. These teams include patient navigators who provided in-depth information about clinical trials to prospective patients and support them during their treatment. They also include pharmacists who work with patients’ cells or manufactured stem cell-products before the therapies are given to patients. And lastly, let’s not forget the doctors and nurses that are specially trained in the delivery of stem cell therapies to patients.

The Alpha Clinics Network also offers resources and tools for clinical trial sponsors, the people responsible for conducting the trials. These include patient education and recruitment tools and access to over 20 million patients in California to support successful recruitment. And because the different clinical trial sites are in the same network, sponsors can benefit from sharing the same approval measures for a single trial at multiple sites.

Looking at the big picture, our Alpha Clinics Network provides a platform where patients can access the latest stem cell treatments, and sponsors can access expert teams at multiple medical centers to increase the likelihood that their trial succeeds.

The Alpha Clinics Network is expanding

This collective expertise has resulted in a 3-fold (from 12 to 36 – two trials are being conducted at two sites) increase in the number of stem cell clinical trials at the Alpha Clinic sites since the Network’s inception. And the number continues to rise every quarter. Given this impressive track record, CIRM’s Board voted in February to expand our Alpha Clinics Network. The Board approved up to $16 million to be awarded to two additional medical centers ($8 million each) to create new Alpha Clinic sites and work with the current Network to accelerate patient access to stem cell treatments.

CIRM’s Chairman Jonathan Thomas explained,

Jonathan Thomas

“We laid down the foundation for conducting high quality stem cell trials when we started this network in 2014. The success of these clinics in less than three years has prompted the CIRM Board to expand the Network to include two new trial sites. With this expansion, CIRM is building on the current network’s momentum to establish new and better ways of treating patients with stem cell-based therapies.”

The Alpha Clinics Network plays a vital role in CIRM’s five-year strategic plan to fund 50 new clinical trials by 2020. In fact, the Alpha Clinic Network supports clinical trials funded by CIRM, industry sponsors and other sources. Thus, the Network is on track to becoming a sustainable resource to deliver stem cell treatments indefinitely.

In addition to expanding CIRM’s Network, the new sites will develop specialized programs to train doctors in the design and conduct of stem cell clinical trials. This training will help drive the development of new stem cell therapies at California medical centers.

Apply to be one our new Alpha Clinics!

For the medical centers interested in joining the CIRM Alpha Stem Cell Clinics Network, the deadline for applications is May 15th, 2017. Details on this funding opportunity can be found on our funding page.

The CIRM Team looks forward to working with prospective applicants to address any questions. The Alpha Stem Cell Clinics Network will also be showcasing it achievement at its Second Annual Symposium, details may be found on the City of Hope Alpha Clinics website.

City of Hope Medical Center and Alpha Stem Cell Clinic


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