When Google turns on you, you know you are in trouble

For years CIRM and others in the stem cell community (hello Paul Knoepfler) have been warning people about the dangers of going to clinics offering unproven and unapproved stem cell therapies. Recently the drum beat of people and organizations coming out in support of that stand has grown louder and louder. Mainstream media – TV and print – have run articles about these predatory clinics. And now, Google has joined those ranks, announcing it will restrict ads promoting these clinics.

“We regularly review and revise our advertising policies. Today, we’re announcing a new Healthcare and medicines policy to prohibit advertising for unproven or experimental medical techniques such as most stem cell therapy, cellular (non-stem) therapy, and gene therapy.”

Deepak Srivastava: Photo courtesy Gladstone Institutes

The president of the International Society for Stem Cell Research (ISSCR) Dr. Deepak Srivastava quickly issued a statement of support, saying:

“Google’s new policy banning advertising for speculative medicines is a much-needed and welcome step to curb the marketing of unscrupulous medical products such as unproven stem cell therapies. While stem cells have great potential to help us understand and treat a wide range of diseases, most stem cell interventions remain experimental and should only be offered to patients through well-regulated clinical trials. The premature marketing and commercialization of unproven stem cell products threatens public health, their confidence in biomedical research, and undermines the development of legitimate new therapies.”

Speaking of Deepak – we can use first names here because we are not only great admirers of him as a physician but also as a researcher, which is why we have funded some of his research – he has just published a wonderfully well written article criticizing these predatory clinics.

The article – in Scientific American – is titled “Don’t Believe Everything You Hear About Stem Cells” and rather than paraphrase his prose, I think it best if you read it yourself. So, here it is.

Enjoy.

Don’t Believe Everything You Hear about Stem Cells

The science is progressing rapidly,but bad actors have co-opted stem cells’ hope and promise by preying on unsuspecting patients and their families

Stem cell science is moving forward rapidly, with potential therapies to treat intractable human diseases on the horizon.Clinical trials are now underway to test the safety and effectiveness of stem cell–based treatments for blindness,spinal cord injury,heart disease,Parkinson’s disease, and more,some with early positive results.A sense of urgency drives the scientific community, and there is tremendous hope to finally cure diseases that, to date, have had no treatment.


But don’t believe everything you hear about stem cells. Advertisements and pseudo news articles promote stem cell treatments for everything from Alzheimer’s disease,autism and ALS, to cerebral palsy and other diseases.The claims simply aren’t true–they’re propagated by people wanting to make money off of a desperate and unsuspecting or unknowing public.Patients and their families can be misled by deceptive marketing from unqualified physicians who often don’t have appropriate medical credentials and offer no scientific evidence of their claims.In many cases, the cells being utilized are not even true stem cells.

Advertisements for stem cell treatments are showing up everywhere, with too-good-to-be-true claims and often a testimonial or two meant to suggest legitimacy or efficacy.Beware of the following:

    •       Claims that stem cell treatments can treat a wide range of diseases using a singular stem cell type. This is unlikely to be true.

    •       Claims that stem cells taken from one area of the body can be used to treat another, unrelated area of the body. This is also unlikely to be true.     •       Patient testimonials used to validate a particular treatment, with no scientific evidence. This is a red flag.

    •       Claims that evidence doesn’t yet exist because the clinic is running a patient-funded trial. This is a red flag; clinical trials rarely require payment for experimental treatment.

    •       Claims that the trial is listed on ClinicalTrials.gov and is therefore NIH-approved. This may not be true. The Web site is simply a listing; not all are legitimate trials.

    •       The bottom line: Does the treatment sound too good to be true? If so, it probably is. Look for concrete evidence that the treatment works and is safe.

Hundreds of clinics offer costly, unapproved and unproven stem cell interventions, and patients may suffer physical and financial harm as a result.A Multi-Pronged Approach to Deal with Bad Actors 

The International Society for Stem Cell Research (ISSCR)has long been concerned that bad actors have co-opted the hope and promise of stem cell science to prey on unsuspecting patients and their families.

We read with sadness and disappointment the many stories of people trying unproven therapies and being harmed, including going blind from injections into the eyes or suffering from a spinal tumor after an injection of stem cells.Patients left financially strapped, with no physical improvement in their condition and no way to reclaim their losses, are an underreported and underappreciated aspect of these treatments.

Since late 2017, the Food and Drug Administration has stepped up its regulatory enforcement of stem cell therapies and provided a framework for regenerative medicine products that provides guidelines for work in this space.The agency has alerted many clinics and centers that they are not in compliance and has pledged to bring additional enforcement action if needed.

A Multi-Pronged Approach to Deal with Bad Actors  The International Society for Stem Cell Research (ISSCR) has long been concerned that bad actors have co-opted the hope and promise of stem cell science to prey on unsuspecting patients and their families.

We read with sadness and disappointment the many stories of people trying unproven therapies and being harmed, including going blind from injections into the eyesor suffering from a spinal tumor after an injection of stem cells.Patients left financially strapped, with no physical improvement in their condition and no way to reclaim their losses, are an underreported and underappreciated aspect of these treatments.

Since late 2017, the Food and Drug Administration has stepped up its regulatory enforcement of stem cell therapies and provided a framework for regenerative medicine products that provides guidelines for work in this space.The agency has alerted many clinics and centers that they are not in compliance and has pledged to bring additional enforcement action if needed.

In recent weeks, a federal judge granted the FDA a permanent injunction against U.S. Stem Cell, Inc. and U.S. Stem Cell Clinic, LLC for adulterating and misbranding its cellular products and operating outside of regulatory authority.We hope this will send a strong message to other clinics misleading patients with unapproved and potentially harmful cell-based products.

The Federal Trade Commission has also helped by identifying and curtailing unsubstantiated medical claims in advertising by several clinics. Late in 2018 the FTC won a $3.3-million judgment against two California-based clinics for deceptive health claims. The Federal Trade Commission has also helped by identifying and curtailing unsubstantiated medical claims in advertising by several clinics. Late in 2018 the FTC won a $3.3-million judgment against two California-based clinics for deceptive health claims.

These and other actions are needed to stem the tide of clinics offering unproved therapies and the people who manage and operate them.

Improving Public Awareness

We’re hopeful that the FDA will help improve public awareness of these issues and curb the abuses on ClinicalTrials.gov,a government-run Web site being misused by rogue clinics looking to legitimize their treatments. They list pay-to-participate clinical trials on the site, often without developing, registering or administering a real clinical trial.

The ISSCR Web site A Closer Look at Stem Cellsincludes patient-focused information about stem cells,with information written and vetted by stem cell scientists.The site includes how and where to report adverse events and false marketing claims by stem cell clinics.I encourage you to visit and learn about what is known and unknown about stem cells and their potential for biomedicine.The views expressed are those of the author(s) and are not necessarily those of Scientific American.

Moving a great idea targeting diabetes out of the lab and into a company

Tejal Desai in her lab at UCSF: Photo courtesy Todd Dubnicoff

It’s always gratifying to see research you have helped support go from being an intriguing idea to something with promise to a product that is now the focus of a company. It’s all the more gratifying if the product in question might one day help millions of people battling diabetes.

That’s the case with a small pouch being developed by a company called Encellin. The pouch is the brainchild of Tejal Desai, Ph.D., a professor of bioengineering at UCSF and a CIRM grantee.

Encellin’s encapsulation device

“It’s a cell encapsulation device, so this material can essentially protect beta cells from the immune system while allowing them to function by secreting insulin. We are placing stem cell-derived beta cells into the pouch which is then implanted under the skin. The cells are then able to respond to changes in sugar or glucose levels in the blood by pumping out insulin.  By placing the device in a place that is accessible we can easily remove it if we have to, but also we can recharge it and put in new cells as well.”

While the pouch was developed in Dr. Desai’s lab, the idea to take it from a promising item and try to turn it into a real-world therapy came from one of Dr. Desai’s former students, Crystal Nyitray, Ph.D.

Crystal Nyitray: Photo courtesy FierceBiotech

After getting her PhD, Nyitray went to work for the pharmaceutical giant Sanofi. In an article in FierceBiotech she says that’s where she realized that the pouch she had been working on at UCSF had real potential.

“During that time, I started to realize we really had something, that everything that pharma or biotech was looking at was something we had been developing from the ground up with those specific questions in mind,”

So Dr. Nyitray went to work for QB3, the institute created by UC San Francisco to help startups develop their ideas and get funding. The experience she gained there gave her the confidence to be the co-founder and CEO of Encellin.

Dr. Desai is a scientific advisor to Encellin. She says trying to create a device that contains insulin-secreting cells is not new. Many previous attempts failed because once the device was placed in the body, the immune system responded by creating fibrosis or scarring around it which blocked the ability of the cells to get out.

But she thinks their approach has an advantage over previous attempts.

“This is not a new idea, the idea has been around for 40 or more years but getting it to work is hard. We have a convergence of getting the right cell types and combining that with our knowledge of immunology and then the material science where we can design materials at this scale to get the kind of function that we need.

Dr. Nyitray ““If we can reduce fibrosis, it really helps the cells get nutrients better, survive better and signal more effectively. It’s really critical to their success.”

Dr. Desai says the device is still in the early stages of being tested, but already it’s showing promise.

“We have done testing in animals. Where the company is taking this is now to see if we can take this to larger animals and then ultimately people.”

She says without CIRM’s support none of this would have happened.

“CIRM has been really instrumental in helping us refine the cell technology piece of it, to get really robust cells and also to support the development to push the materials, to understand the biology, to really understand what was happening with the cell material interface. We know we have a lot of challenges ahead, but we are really excited to see if this could work.”

We are excited too. We are looking forward to seeing what Encellin does in the coming years. It could change the lives of millions of people around the world.

No pressure. 

“Brains” in a dish that can create electrical impulses

Brain organoids in a petri dish: photo courtesy UCSD

For several years, researchers have been able to take stem cells and use them to make three dimensional structures called organoids. These are a kind of mini organ that scientists can then use to study what happens in the real thing. For example, creating kidney organoids to see how kidney disease develops in patients.

Scientists can do the same with brain cells, creating clumps of cells that become a kind of miniature version of parts of the brain. These organoids can’t do any of the complex things our brains do – such as thinking – but they do serve as useful physical models for us to use in trying to develop a deeper understanding of the brain.

Now Alysson Muotri and his team at UC San Diego – in a study supported by two grants from CIRM – have taken the science one step further, developing brain organoids that allow us to measure the level of electrical activity they generate, and then compare it to the electrical activity seen in the developing brain of a fetus. That last sentence might cause some people to say “What?”, but this is actually really cool science that could help us gain a deeper understanding of how brains develop and come up with new ways to treat problems in the brain caused by faulty circuitry, such as autism or schizophrenia.

The team developed new, more effective methods of growing clusters of the different kinds of cells found in the brain. They then placed them on a multi-electrode array, a kind of muffin tray that could measure electrical impulses. As they fed the cells and increased the number of cells in the trays they were able to measure changes in the electrical impulses they gave off. The cells went from producing 3,000 spikes a minute to 300,000 spikes a minute. This is the first time this level of activity has been achieved in a cell-based laboratory model. But that’s not all.

When they further analyzed the activity of the organoids, they found there were some similarities to the activity seen in the brains of premature babies. For instance, both produced short bursts of activity, followed by a period of inactivity.

Alysson Muotri

In a news release Muotri says they were surprised by the finding:

“We couldn’t believe it at first — we thought our electrodes were malfunctioning. Because the data were so striking, I think many people were kind of skeptical about it, and understandably so.”

Muotri knows that this research – published in the journal Cell Stem Cell – raises ethical issues and he is quick to say that these organoids are nothing like a baby’s brain, that they differ in several critical ways. The organoids are tiny, not just in size but also in the numbers of cells involved. They also don’t have blood vessels to keep them alive or help them grow and they don’t have any ability to think.

“They are far from being functionally equivalent to a full cortex, even in a baby. In fact, we don’t yet have a way to even measure consciousness or sentience.”

What these organoids do have is the ability to help us look at the structure and activity of the brain in ways we never could before. In the past researchers depended on mice or other animals to test new ideas or therapies for human diseases or disorders. Because our brains are so different than animal brains those approaches have had limited results. Just think about how many treatments for Alzheimer’s looked promising in animal models but failed completely in people.

These new organoids allow us to explore how new therapies might work in the human brain, and hopefully increase our ability to develop more effective treatments for conditions as varied as epilepsy and autism.

Time and money and advancing stem cell research

The human genome

Way back in the 1990’s scientists were hard at work decoding the human genome, trying to map and understand all the genes that make up people. At the time there was a sense of hope, a feeling that once we had decoded the genome, we’d have cures for all sorts of things by next Thursday. It didn’t quite turn out that way.

The same was true for stem cell research. In the early days there was a strong feeling that this was going to quite quickly produce new treatments and cures for diseases ranging from Parkinson’s and Alzheimer’s to heart disease and stroke. Although we have made tremendous strides we are still not where we hoped we’d be.

It’s a tough lesson to learn, but an important one: good scientific research moves at its own pace and pays little heed to our hopes or desires. It takes time, often a long time, and money, usually a lot of money, to develop new treatments for deadly diseases and disorders.

Many people, particularly those battling deadly diseases who are running out of time, are frustrated at the slow pace of stem cell research, at the years and years of work that it takes to get even the most promising therapy into a clinical trial where it can be tested in people. That’s understandable. If your life is on the line, it’s difficult to be told that you have to be patient. Time is a luxury many patients don’t have.

But that caution is necessary. The last thing we want to do is rush to test something in people that isn’t ready. And stem cells are a whole new way of treating disease, using cells that may stay in the body for years, so we really need to be sure we have done everything we can to ensure they are safe before delivering them to people.

The field of gene therapy was set back years after one young patient, Jesse Gelsinger, died as a result of an early experimental treatment. We don’t want the same to happen to stem cell research.

And yet progress is being made, albeit not as quickly as any of us would like. At the end of the first ten years of CIRM’s existence we had ten projects that we supported that were either in, or applying to be in, a clinical trial sanctioned by the US Food and Drug Administration (FDA). Five years later that number is 56.

Most of those are in Phase 1 or 2 clinical trials which means they are still trying to show they are both safe and effective enough to be made available to a wider group of people. However, some of our projects are in Phase 3, the last step before, hopefully, being given FDA approval to be made more widely available and – just as important – to be covered by insurance.

Other CIRM-funded projects have been given Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA, a new program that allows projects that show they are safe and benefit patients in early stage clinical trials, to apply for priority review, meaning they could get approved faster than normal. Out of 40 RMAT designations awarded so far, six are for CIRM projects.

We are working hard to live up to our mission statement of accelerating stem cell treatments to patients with unmet medical needs. We have been fortunate in having $3 billion to spend on advancing this research in California; an amount no other US state, indeed few other countries, have been able to match. Yet even that amount is tiny compared to the impact that many of these diseases have. For example, the economic cost of treating diabetes in the US is a staggering $327 billion a year.

The simple truth is that unless we, as a nation, invest much more in scientific research, we are not going to be able to develop cures and new, more effective, treatments for a wide range of diseases.

Time and money are always going to be challenging when it comes to advancing stem cell research and bringing treatments to patients. With greater knowledge and understanding of stem cells and how best to use them we can speed up the timeline. But without money none of that can happen.

Our blog is just one of many covering the topic of “What are the hurdles impacting patient access to cell and gene therapies as part of Signal’s fourth annual blog carnival.

Boosting the blood system after life-saving therapy

Following radiation, the bone marrow shows nearly complete loss of blood cells in mice (left). Mice treated with the PTP-sigma inhibitor displayed rapid recovery of blood cells (purple, right): Photo Courtesy UCLA

Chemotherapy and radiation are two of the front-line weapons in treating cancer. They can be effective, even life-saving, but they can also be brutal, taking a toll on the body that lasts for months. Now a team at UCLA has developed a therapy that might enable the body to bounce back faster after chemo and radiation, and even make treatments like bone marrow transplants easier on patients.

First a little background. Some cancer treatments use chemotherapy and radiation to kill the cancer, but they can also damage other cells, including those in the bone marrow responsible for making blood stem cells. Those cells eventually recover but it can take weeks or months, and during that time the patient may feel fatigue and be more susceptible to infections and other problems.

In a CIRM-supported study, UCLA’s Dr. John Chute and his team developed a drug that speeds up the process of regenerating a new blood supply. The research is published in the journal Nature Communications.

They focused their attention on a protein called PTP-sigma that is found in blood stem cells and acts as a kind of brake on the regeneration of those cells. Previous studies by Dr. Chute showed that, after undergoing radiation, mice that have less PTP-sigma were able to regenerate their blood stem cells faster than mice that had normal levels of the protein.

John Chute: Photo courtesy UCLA

So they set out to identify something that could help reduce levels of PTP-sigma without affecting other cells. They first identified an organic compound with the charming name of 6545075 (Chembridge) that was reported to be effective against PTP-sigma. Then they searched a library of 80,000 different small molecules to find something similar to 6545075 (and this is why science takes so long).

From that group they developed more than 100 different drug candidates to see which, if any, were effective against PTP-sigma. Finally, they found a promising candidate, called DJ009. In laboratory tests DJ009 proved itself effective in blocking PTP-sigma in human blood stem cells.

They then tested DJ009 in mice that were given high doses of radiation. In a news release Dr. Chute said the results were very encouraging:

“The potency of this compound in animal models was very high. It accelerated the recovery of blood stem cells, white blood cells and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”

Of the radiated mice, most that were given DJ009 survived. In comparison, those that didn’t get DJ009 died within three weeks.

They saw similar benefits in mice given chemotherapy. Mice with DJ009 saw their white blood cells – key components of the immune system – return to normal within two weeks. The untreated mice had dangerously low levels of those cells at the same point.

It’s encouraging work and the team are already getting ready for more research so they can validate their findings and hopefully take the next step towards testing this in people in clinical trials.

Stem cell progress and promise in fighting leukemia

Computer illustration of a cancerous white blood cell in leukemia.

There is nothing you can do to prevent or reduce your risk of leukemia. That’s not a very reassuring statement considering that this year alone almost 62,000 Americans will be diagnosed with leukemia; almost 23,000 will die from the disease. That’s why CIRM is funding four clinical trials targeting leukemia, hoping to develop new approaches to treat, and even cure it.

That’s also why our next special Facebook Live “Ask the Stem Cell Team” event is focused on this issue. Join us on Thursday, August 29th from 1pm to 2pm PDT to hear a discussion about the progress in, and promise of, stem cell research for leukemia.

We have two great panelists joining us:

Dr. Crystal Mackall, has many titles including serving as the Founding Director of the Stanford Center for Cancer Cell Therapy.  She is using an innovative approach called a Chimeric Antigen Receptor (CAR) T Cell Therapy. This works by isolating a patient’s own T cells (a type of immune cell) and then genetically engineering them to recognize a protein on the surface of cancer cells, triggering their destruction. This is now being tested in a clinical trial funded by CIRM.

Natasha Fooman. To describe Natasha as a patient advocate would not do justice to her experience and expertise in fighting blood cancer and advocating on behalf of those battling the disease. For her work she has twice been named “Woman of the Year” by the Leukemia and Lymphoma Society. In 2011 she was diagnosed with a form of lymphoma that was affecting her brain. Over the years, she would battle lymphoma three times and undergo chemotherapy, radiation and eventually a bone marrow transplant. Today she is cancer free and is a key part of a CIRM team fighting blood cancer.

We hope you’ll join us to learn about the progress being made using stem cells to combat blood cancers, the challenges ahead but also the promising signs that we are advancing the field.

We also hope you’ll take an active role by posting questions on Facebook during the event, or sending us questions ahead of time to info@cirm.ca.gov. We will do our best to address as many as we can.

Here’s the link to the event, feel free to share this with anyone you think might be interested in joining us for Facebook Live “Ask the Stem Cell Team about Leukemia”

One family’s fight to save their son’s life, and how stem cells made it possible

CIRM’s mission is very simple: to accelerate stem cell treatments to patients with unmet medical needs. Anne Klein’s son, Everett, was a poster boy for that statement. Born with a fatal immune disorder Everett faced a bleak future. But Anne and husband Brian were not about to give up. The following story is one Anne wrote for Parents magazine. It’s testament to the power of stem cells to save lives, but even more importantly to the power of love and the determination of a family to save their son.

My Son Was Born With ‘Bubble Boy’ Disease—But A Gene Therapy Trial Saved His Life

Everett Schmitt. Photo: Meg Kumin

I wish more than anything that my son Everett had not been born with severe combined immunodeficiency (SCID). But I know he is actually one of the lucky unlucky ones. By Anne Klein

As a child in the ’80s, I watched a news story about David Vetter. David was known as “the boy in the bubble” because he was born with severe combined immunodeficiency (SCID), a rare genetic disease that leaves babies with very little or no immune system. To protect him, David lived his entire life in a plastic bubble that kept him separated from a world filled with germs and illnesses that would have taken his life—likely before his first birthday.

I was struck by David’s story. It was heartbreaking and seemed so otherworldly. What would it be like to spend your childhood in an isolation chamber with family, doctors, reporters, and the world looking in on you? I found it devastating that an experimental bone marrow transplant didn’t end up saving his life; instead it led to fatal complications. His mother, Carol Ann Demaret, touched his bare hand for the first and last time when he was 12 years old.

I couldn’t have known that almost 30 years later, my own son, Everett, would be born with SCID too.

Everett’s SCID diagnosis

At birth, Everett was big, beautiful, and looked perfectly healthy. My husband Brian and I already had a 2-and-a-half-year-old son, Alden, so we were less anxious as parents when we brought Everett home. I didn’t run errands with Alden until he was at least a month old, but Everett was out and about with us within a few days of being born. After all, we thought we knew what to expect.

But two weeks after Everett’s birth, a doctor called to discuss Everett’s newborn screening test results. I listened in disbelief as he explained that Everett’s blood sample indicated he may have an immune deficiency.

“He may need a bone marrow transplant,” the doctor told me.

I was shocked. Everett’s checkup with his pediatrician just two days earlier went swimmingly. I hung up and held on to the doctor’s assurance that there was a 40 percent chance Everett’s test result was a false positive.

After five grueling days of waiting for additional test results and answers, I received the call: Everett had virtually no immune system. He needed to be quickly admitted to UCSF Benioff Children’s Hospital in California so they could keep him isolated and prepare to give him a stem cell transplant. UCSF diagnosed him specifically with SCID-X1, the same form David battled.

Beginning SCID treatment

The hospital was 90 miles and more than two hours away from home. Our family of four had to be split into two, with me staying in the hospital primarily with Everett and Brian and Alden remaining at home, except for short visits. The sudden upheaval left Alden confused, shaken, and sad. Brian and I quickly transformed into helicopter parents, neurotically focused on every imaginable contact with germs, even the mildest of which could be life-threatening to Everett.

When he was 7 weeks old, Everett received a stem cell transplant with me as his donor, but the transplant failed because my immune cells began attacking his body. Over his short life, Everett has also spent more than six months collectively in the hospital and more than three years in semi-isolation at home. He’s endured countless biopsies, ultrasounds, CT scans, infusions, blood draws, trips to the emergency department, and medical transports via ambulance or helicopter.

Gene therapy to treat SCID

At age 2, his liver almost failed and a case of pneumonia required breathing support with sedation. That’s when a doctor came into the pediatric intensive care unit and said, “When Everett gets through this, we need to do something else for him.” He recommended a gene therapy clinical trial at the National Institutes of Health (NIH) that was finally showing success in patients over age 2 whose transplants had failed. This was the first group of SCID-X1 patients to receive gene therapy using a lentiviral vector combined with a light dose of chemotherapy.

After the complications from our son’s initial stem cell transplant, Brian and I didn’t want to do another stem cell transplant using donor cells. My donor cells were at war with his body and cells from another donor could do the same. Also, the odds of Everett having a suitable donor on the bone marrow registry were extremely small since he didn’t have one as a newborn. At the NIH, he would receive a transplant with his own, perfectly matched, gene-corrected cells. They would be right at home.

Other treatment options would likely only partially restore his immunity and require him to receive infusions of donor antibodies for life, as was the case with his first transplant. Prior gene therapy trials produced similarly incomplete results and several participants developed leukemia. The NIH trial was the first one showing promise in fully restoring immunity, without a risk of cancer. Brian and I felt it was Everett’s best option. Without hesitation, we flew across the country for his treatment. Everett received the gene therapy in September 2016 when he was 3, becoming the youngest patient NIH’s clinical trial has treated.

Everett’s recovery

It’s been more than two years since Everett received gene therapy and now more than ever, he has the best hope of developing a fully functioning immune system. He just received his first vaccine to test his ability to mount a response. Now 6 years old, he’s completed kindergarten and has been to Disney World. He plays in the dirt and loves shows and movies from the ’80s (maybe some of the same ones David enjoyed).

Everett knows he has been through a lot and that his doctors “fixed his DNA,” but he’s focused largely on other things. He’s vocal when confronted with medical pain or trauma, but seems to block out the experiences shortly afterwards. It’s sad for Brian and me that Everett developed these coping skills at such a young age, but we’re so grateful he is otherwise expressive and enjoys engaging with others. Once in the middle of the night, he woke us up as he stood in the hallway, exclaiming, “I’m going back to bed, but I just want you to know that I love you with all my heart!”

I wish more than anything that Everett had not been born with such a terrible disease and I could erase all the trauma, isolation, and pain. But I know that he is actually one of the lucky unlucky ones. Everett is fortunate his disease was caught early by SCID newborn screening, which became available in California not long before his birth. Without this test, we would not have known he had SCID until he became dangerously ill. His prognosis would have been much worse, even under the care of his truly brilliant and remarkable doctors, some of whom cared for David decades earlier.

Carol-Ann-mother-of-David-Vetter-meeting-Everett-Schmitt
Everett Schmitt meeting David Vetter’s mom Carol Ann Demaret. Photo – Brian Schmitt

When Everett was 4, soon after the gene therapy gave him the immunity he desperately needed, our family was fortunate enough to cross paths with David’s mom, Carol Ann, at an Immune Deficiency Foundation event. Throughout my life, I had seen her in pictures and on television with David. In person, she was warm, gracious, and humble. When I introduced her to Everett and explained that he had SCID just like David, she looked at Everett with loving eyes and asked if she could touch him. As she touched Everett’s shoulder and they locked eyes, Brian and I looked on with profound gratitude.

Anne Klein is a parent, scientist, and a patient advocate for two gene therapy trials funded by the California Institute for Regenerative Medicine. She is passionate about helping parents of children with SCID navigate treatment options for their child.

You can read about the clinical trials we are funding for SCID here, here, here and here.

How stem cells know the right way to make a heart . And what goes wrong when they don’t

Gladstone scientists Deepak Srivastava (left), Yvanka De Soysa (center), and Casey Gifford (right) publish a complete catalog of the cells involved in heart development.

The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.

In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.

In a story in Science and Research Technology News, Casey Gifford, a senior author on the study, said this approach helps pinpoint genetic variants that might be causing problems.

“This sequencing technique allowed us to see all the different types of cells present at various stages of heart development and helped us identify which genes are activated and suppressed along the way. We were not only able to uncover the existence of unknown cell types, but we also gained a better understanding of the function and behavior of individual cells—information we could never access before.”

Then they partnered with a team at Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg which ran a computational analysis to identify which genes were involved in creating different cell types. This highlighted one specific gene, called Hand2, that controls the activity of thousands of other genes. They found that a lack of Hand2 in mice led to an inability to form one of the heart’s chambers, which in turn led to impaired blood flow to the lungs. The embryo was creating the cells needed to form the chamber, but not a critical pathway that would allow those cells to get where they were needed when they were needed.

Gifford says this has given us a deeper insight into how cells are formed, knowledge we didn’t have before.

“Single-cell technologies can inform us about how organs form in ways we couldn’t understand before and can provide the underlying cause of disease associated with genetic variations. We revealed subtle differences in very, very small subsets of cells that actually have catastrophic consequences and could easily have been overlooked in the past. This is the first step toward devising new therapies.”

These therapies are needed to help treat congenital heart defects, which are the most common and deadly birth defects. There are more than 2.5 million Americans with these defects. Deepak Srivastava, President of Gladstone and the leader of the study, said the knowledge gained in this study could help developed strategies to help address that.

“We’re beginning to see the long-term consequences in adults, and right now, we don’t really have any way to treat them. My hope is that if we can understand the genetic causes and the cell types affected, we could potentially intervene soon after birth to prevent the worsening of their state over time.

The study is published in the journal Nature.

CIRM Board Approves New Clinical Trial for Breast Cancer Related Brain Metastases

Dr. Saul Priceman

Yesterday the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $9.28 million to Dr. Saul Priceman at City of Hope to conduct a clinical trial for the treatment of breast cancer related brain metastases, which are tumors in the brain that have spread from the original site of the breast cancer.

This award brings the total number of CIRM-funded clinical trials to 56. 

Breast cancer is the second-most common cancer in women, both in the United States (US) and worldwide.  It is estimated that over 260,000 women in the US will be diagnosed with breast cancer in 2019 and 1 out of 8 women in the US will get breast cancer at some point during her lifetime. Some types of breast cancer have a high likelihood of metastasizing to the brain.  When that happens, there are few treatment options, leading to a poor prognosis and poor quality of life. 

Dr. Priceman’s clinical trial is testing a therapy to treat brain metastases that came from breast cancers expressing high levels of a protein called HER2.   The therapy consists of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells.  The T cells are modified with a protein called a chimeric antigen receptor (CAR) that recognizes the tumor protein HER2.  These modified T cells (CAR-T cells) are then infused into the patient’s brain where they are expected to detect and destroy the HER2-expressing tumors in the brain.

CIRM has also funded the earlier work related to this study, which was critical in preparing the therapy for Food and Drug Administration (FDA) approval for permission to start a clinical trial in people.

“When a patient is told that their cancer has metastasized to other areas of the body, it can be devastating news,” says Maria T. Millan, M.D., the President and CEO of CIRM.  “There are few options for patients with breast cancer brain metastases.  Standard of care treatments, which include brain irradiation and chemotherapy, have associated neurotoxicity and do little to improve survival, which is typically no more than a few months.  CAR-T cell therapy is an exciting and promising approach that now offers us a more targeted approach to address this condition.”

The CIRM Board also approved investing $19.7 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Dr. Mark Tuszynski at the University of California San Diego (UCSD) was awarded $6.23 million to develop a therapy for spinal cord injury (SCI). Dr. Tuszynski will use human embryonic stem cells (hESCs) to create neural stem cells (NSCs) which will then be grafted at the injury site.  In preclinical studies, the NSCs have been shown to help create a kind of relay at the injury site, restoring communication between the brain and spinal cord and re-establishing muscle control and movement.

Dr. Mark Humayun at the University of Southern California (USC) was awarded $3.73 million to develop a novel therapeutic product capable of slowing the progression of age-related macular degeneration (AMD), the leading cause of vision loss in the US.

The approach that Dr. Humayun is developing will use a biologic product produced by human embryonic stem cells (hESCs). This material will be injected into the eye of patients with early development of dry AMD, supporting the survival of photoreceptors in the affected retina, the kind of cells damaged by the disease.

The TRAN1 awards went to:

Stay tuned for our next blog which will dive into each of these awards in much more detail.

From bench to bedside: a Q&A with stem cell expert Jan Nolta

At CIRM we are privileged to work with many remarkable people who combine brilliance, compassion and commitment to their search for new therapies to help people in need. One of those who certainly fits that description is UC Davis’ Jan Nolta.

This week the UC Davis Newsroom posted a great interview with Jan. Rather than try and summarize what she says I thought it would be better to let her talk for herself.

Jan Nolta
Jan Nolta

Talking research, unscrupulous clinics, and sustaining the momentum

(SACRAMENTO) —

In 2007, Jan Nolta returned to Northern California from St. Louis to lead what was at the time UC Davis’ brand-new stem cell program. As director of the UC Davis Stem Cell Program and the Institute for Regenerative Cures, she has overseen the opening of the institute, more than $140 million in research grants, and dozens upon dozens of research studies. She recently sat down to answer some questions about regenerative medicine and all the work taking place at UC Davis Health.

Q: Turning stem cells into cures has been your mission and mantra since you founded the program. Can you give us some examples of the most promising research?

I am so excited about our research. We have about 20 different disease-focused teams. That includes physicians, nurses, health care staff, researchers and faculty members, all working to go from the laboratory bench to patient’s bedside with therapies.

Perhaps the most promising and exciting research right now comes from combining blood-forming

stem cells with gene therapy. We’re working in about eight areas right now, and the first cure, something that we definitely can call a stem cell “cure,” is coming from this combined approach.

Soon, doctors will be able to prescribe this type of stem cell therapy. Patients will use their own bone marrow or umbilical cord stem cells. Teams such as ours, working in good manufacturing practice facilities, will make vectors, essentially “biological delivery vehicles,” carrying a good copy of the broken gene. They will be reinserted into a patient’s cells and then infused back into the patient, much like a bone marrow transplant.

“Perhaps the most promising and exciting research right now comes from combining blood-forming stem cells with gene therapy.”

Along with treating the famous bubble baby disease, where I had started my career, this approach looks very promising for sickle cell anemia. We’re hoping to use it to treat several different inherited metabolic diseases. These are conditions characterized by an abnormal build-up of toxic materials in the body’s cells. They interfere with organ and brain function. It’s caused by just a single enzyme. Using the combined stem cell gene therapy, we can effectively put a good copy of the gene for that enzyme back into a patient’s bone marrow stem cells. Then we do a bone marrow transplantation and bring back a person’s normal functioning cells.

The beauty of this therapy is that it can work for the lifetime of a patient. All of the blood cells circulating in a person’s system would be repaired. It’s the number one stem cell cure happening right now. Plus, it’s a therapy that won’t be rejected. These are a patient’s own stem cells. It is just one type of stem cell, and the first that’s being commercialized to change cells throughout the body.

Q: Let’s step back for a moment. In 2004, voters approved Proposition 71. It has funded a majority of the stem cell research here at UC Davis and throughout California. What’s been the impact of that ballot measure and how is it benefiting patients?

We have learned so much about different types of stem cells, and which stem cell will be most appropriate to treat each type of disease. That’s huge. We had to first do that before being able to start actual stem cell therapies. CIRM [California Institute for Regenerative Medicine] has funded Alpha Stem Cell Clinics. We have one of them here at UC Davis and there are only five in the entire state. These are clinics where the patients can go for high-quality clinical stem cell trials approved by the FDA [U.S. Food and Drug Administration]. They don’t need to go to “unapproved clinics” and spend a lot of money. And they actually shouldn’t.

“By the end of this year, we’ll have 50 clinical trials.”

By the end of this year, we’ll have 50 clinical trials [here at UC Davis Health]. There are that many in the works.

Our Alpha Clinic is right next to the hospital. It’s where we’ll be delivering a lot of the immunotherapies, gene therapies and other treatments. In fact, I might even get to personally deliver stem cells to the operating room for a patient. It will be for a clinical trial involving people who have broken their hip. It’s exciting because it feels full circle, from working in the laboratory to bringing stem cells right to the patient’s bedside.

We have ongoing clinical trials for critical limb ischemia, leukemia and, as I mentioned, sickle cell disease. Our disease teams are conducting stem cell clinical trials targeting sarcoma, cellular carcinoma, and treatments for dysphasia [a swallowing disorder], retinopathy [eye condition], Duchenne muscular dystrophy and HIV. It’s all in the works here at UC Davis Health.

There’s also great potential for therapies to help with renal disease and kidney transplants. The latter is really exciting because it’s like a mini bone marrow transplant. A kidney recipient would also get some blood-forming stem cells from the kidney donor so that they can better accept the organ and not reject it. It’s a type of stem cell therapy that could help address the burden of being on a lifelong regime of immunosuppressant drugs after transplantation.

Q: You and your colleagues get calls from family members and patients all the time. They frequently ask about stem cell “miracle” cures. What should people know about unproven treatments and unregulated stem cell clinics?

That’s a great question.The number one rule is that if you’re asked to pay money for a stem cell treatment, don’t do it. It’s a big red flag.

When it comes to advertised therapies: “The number one rule is that if you’re asked to pay money for a stem cell treatment, don’t do it. It’s a big red flag.”

Unfortunately, there are unscrupulous people out there in “unapproved clinics” who prey on desperate people. What they are delivering are probably not even stem cells. They might inject you with your own fat cells, which contain very few stem cells. Or they might use treatments that are not matched to the patient and will be immediately rejected. That’s dangerous. The FDA is shutting these unregulated clinics down one at a time. But it’s like “whack-a-mole”: shut one down and another one pops right up.

On the other hand, the Alpha Clinic is part of our mission is to help the public get to the right therapy, treatment or clinical trial. The big difference between those who make patients pay huge sums of money for unregulated and unproven treatments and UC Davis is that we’re actually using stem cells. We produce them in rigorously regulated cleanroom facilities. They are certified to contain at least 99% stem cells.

Patients and family members can always call us here. We can refer them to a genuine and approved clinical trial. If you don’t get stem cells at the beginning [of the clinical trial] because you’re part of the placebo group, you can get them later. So it’s not risky. The placebo is just saline. I know people are very, very desperate. But there are no miracle cures…yet. Clinical trials, approved by the FDA, are the only way we’re going to develop effective treatments and cures.

Q: Scientific breakthroughs take a lot of patience and time. How do you and your colleagues measure progress and stay motivated?   

Motivation?  “It’s all for the patients.”

It’s all for the patients. There are not good therapies yet for many disorders. But we’re developing them. Every day brings a triumph. Measuring progress means treating a patient in a clinical trial, or developing something in the laboratory, or getting FDA approval. The big one will be getting biological license approval from the FDA, which means a doctor can prescribe a stem cell or gene therapy treatment. Then it can be covered by a patient’s health insurance.

I’m a cancer survivor myself, and I’m also a heart patient. Our amazing team here at UC Davis has kept me alive and in great health. So I understand it from both sides. I understand the desperation of “Where do I go?” and “What do I do right now?” questions. I also understand the science side of things. Progress can feel very, very slow. But everything we do here at the Institute for Regenerative Cures is done with patients in mind, and safety.

We know that each day is so important when you’re watching a loved one suffer. We attend patient events and are part of things like Facebook groups, where people really pour their hearts out. We say to ourselves, “Okay, we must work harder and faster.” That’s our motivation: It’s all the patients and families that we’re going to help who keep us working hard.