Using the AIDS virus to help children battling a deadly immune disorder

Ronnie Kashyap, patient in SCID clinical trial: Photo Pawash Priyank

More than 35 million people around the world have been killed by HIV, the virus that causes AIDS. So, it’s hard to think that the same approach the virus uses to infect cells could also be used to help children battling a deadly immune system disorder. But that’s precisely what researchers at UC San Francisco and St. Jude Children’s Research Hospital are doing.

The disease the researchers are tackling is a form of severe combined immunodeficiency (SCID). It’s also known as ‘bubble baby’ disease because children are born without a functioning immune system and in the past were protected from germs within the sterile environment of a plastic bubble. Children with this disease often die of infections, even from a common cold, in the first two years of life.

The therapy involves taking the patient’s own blood stem cells from their bone marrow, then genetically modifying them to correct the genetic mutation that causes SCID. The patient is then given low-doses of chemotherapy to create space in their bone marrow for the news cells. The gene-corrected stem cells are then transplanted back into the infant, creating a new blood supply and a repaired immune system.

Unique delivery system

The novel part of this approach is that the researchers are using an inactivated form of HIV as a means to deliver the correct gene into the patient’s cells. It’s well known that HIV is perfectly equipped to infiltrate cells, so by taking an inactivated form – meaning it cannot infect the individual with HIV – they are able to use that infiltrating ability for good.

The results were announced at the American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta.

The researchers say seven infants treated and followed for up to 12 months, have all produced the three major immune system cell types affected by SCID. In a news release, lead author Ewelina Mamcarz, said all the babies appear to be doing very well:

“It is very exciting that we observed restoration of all three very important cell types in the immune system. This is something that’s never been done in infants and a huge advantage over prior trials. The initial results also suggest our approach is fundamentally safer than previous attempts.”

One of the infants taking part in the trial is Ronnie Kashyap. We posted a video of his story on our blog, The Stem Cellar.

If the stem cell-gene therapy combination continues to show it is both safe and effective it would be a big step forward in treating SCID. Right now, the best treatment is a bone marrow transplant, but only around 20 percent of infants with SCID have a sibling or other donor who is a good match. The other 80 percent have to rely on a less well-matched bone marrow transplant – usually from a parent – that can still leave the child prone to life-threatening infections or potentially fatal complications such as graft-versus-host disease.

CIRM is funding two other clinical trials targeting SCID. You can read about them here and here.

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Progress to a Cure for Bubble Baby Disease

Welcome back to our “Throwback Thursday” series on the Stem Cellar. Over the years, we’ve accumulated an arsenal of exciting stem cell stories about advances towards stem cell-based cures for serious diseases. Today we’re featuring stories about the progress of CIRM-funded clinical trials for the treatment of a devastating, usually fatal, primary immune disease that strikes newborn babies.

evangelina in a bubble

Evie, a former “bubble baby” enjoying life by playing inside a giant plastic bubble

‘Bubble baby disease’ will one day be a thing of the past. That’s a bold statement, but I say it with confidence because of the recent advancements in stem cell gene therapies that are curing infants of this life-threatening immune disease.

The scientific name for ‘bubble baby disease’ is severe combined immunodeficiency (SCID). It prevents the proper development of important immune cells called B and T cells, leaving newborns without a functioning immune system. Because of this, SCID babies are highly susceptible to deadly infections, and without treatment, most of these babies do not live past their first year. Even a simple cold virus can be fatal.

Scientists are working hard to develop stem cell-based gene therapies that will cure SCID babies in their first months of life before they succumb to infections. The technology involves taking blood stem cells from a patient’s bone marrow and genetically correcting the SCID mutation in the DNA of these cells. The corrected stem cells are then transplanted back into the patient where they can grow and regenerate a healthy immune system. Early-stage clinical trials testing these stem cell gene therapies are showing very encouraging results. We’ll share a few of these stories with you below.

CIRM-funded trials for SCID

CIRM is funding three clinical trials, one from UCLA, one at Stanford and one from UCSF & St. Jude Children’s Research Hospital, that are treating different forms of SCID using stem cell gene therapies.

Adenosine Deaminase-Deficient SCID

The first trial is targeting a form of the disease called adenosine deaminase-deficient SCID or ADA-SCID. Patients with ADA-SCID are unable to make an enzyme that is essential for the function of infection-fighting immune cells called lymphocytes. Without working lymphocytes, infants eventually are diagnosed with SCID at 6 months. ADA-SCID occurs in approximately 1 in 200,000 newborns and makes up 15% of SCID cases.

CIRM is funding a Phase 2 trial for ADA-SCID that is testing a stem cell gene therapy called OTL-101 developed by Dr. Don Kohn and his team at UCLA and a company called Orchard Therapeutics. 10 patients were treated in the trial, and amazingly, nine of these patients were cured of their disease. The 10th patient was a teenager who received the treatment knowing that it might not work as it does in infants. You can read more about this trial in our blog from earlier this year.

In a recent news release, Orchard Therapeutics announced that the US Food and Drug Administration (FDA) has awarded Rare Pediatric Disease Designation to OTL-101, meaning that the company will qualify for priority review for drug approval by the FDA. You can read more about what this designation means in this blog.

X-linked SCID

The second SCID trial CIRM is funding is treating patients with X-linked SCID. These patients have a genetic mutation on a gene located on the X-chromosome that causes the disease. Because of this, the disease usually affects boys who have inherited the mutation from their mothers. X-linked SCID is the most common form of SCID and appears in 1 in 60,000 infants.

UCSF and St. Jude Children’s Research Hospital are conducting a Phase 1/2 trial for X-linked SCID. The trial, led by Dr. Brian Sorrentino, is transplanting a patient’s own genetically modified blood stem cells back into their body to give them a healthy new immune system. Patients do receive chemotherapy to remove their diseased bone marrow, but doctors at UCSF are optimizing low doses of chemotherapy for each patient to minimize any long-term effects. According to a UCSF news release, the trial is planning to treat 15 children over the next five years. Some of these patients have already been treated and we will likely get updates on their progress next year.

CIRM is also funding a third clinical trial out of Stanford University that is hoping to make bone marrow transplants safer for X-linked SCID patients. The team, led by Dr. Judy Shizuru, is developing a therapy that will remove unhealthy blood stem cells from SCID patients to improve the survival and engraftment of healthy bone marrow transplants. You can read more about this trial on our clinical trials page.

SCID Patients Cured by Stem Cells

These clinical trial results are definitely exciting, but what is more exciting are the patient stories that we have to share. We’ve spoken with a few of the families whose children participated in the UCLA and UCSF/St. Jude trials, and we asked them to share their stories so that other families can know that there is hope. They are truly inspiring stories of heartbreak and joyful celebration.

Evie is a now six-year-old girl who was diagnosed with ADA-SCID when she was just a few months old. She is now cured thanks to Don Kohn and the UCLA trial. Her mom gave a very moving presentation about Evie’s journey at the CIRM Bridges Trainee Annual Meeting this past July.  You can watch the 20-minute talk below:

Ronnie’s story

Ronnie SCID kid

Ronnie: Photo courtesy Pawash Priyank

Ronnie, who is still less than a year old, was diagnosed with X-linked SCID just days after he was born. Luckily doctors told his parents about the UCSF/St. Jude trial and Ronnie was given the life-saving stem cell gene therapy before he was six months old. Now Ronnie is building a healthy immune system and is doing well back at home with his family. Ronnie’s dad Pawash shared his families moving story at our September Board meeting and you can watch it here.

Our mission at CIRM is to accelerate stem cell treatments to patients with unmet medical needs. We hope that by funding promising clinical trials like the ones mentioned in this blog, that one day soon there will be approved stem cell therapies for patients with SCID and other life-threatening diseases.

Using stem cells to take an inside approach to fixing damaged livers

Often on the Stem Cellar we write about work that is in a clinical trial. But getting research to that stage takes years and years of dedicated work. Over the next few months we are going to profile some of the scientists we fund who are doing Discovery, or early stage research, to highlight the importance of this work in developing the treatments that could ultimately save lives.

 This first profile is by Pat Olson, Ph.D., CIRM’s Vice President of Discovery & Translation

liver

Most of us take our liver for granted.  We don’t think about the fact that our liver carries out more than 500 functions in our bodies such as modifying and removing toxins, contributing to digestion and energy production, and making substances that help our blood to clot.  Without a liver we probably wouldn’t live more than a few days.

Our liver typically functions well but certain toxins, viral infections, long-term excess alcohol consumption and metabolic diseases such as obesity and type 2 diabetes can have devastating effects on it.  Under these conditions, functional liver cells, called hepatocytes, die and are replaced with cells called myofibroblasts.  Myofibroblasts are cells that secrete excess collagen leading to fibrosis, a form of scarring, throughout the liver.  Eventually, a liver transplant is required but the number of donor livers available for transplant is small and the number of persons needing a functional liver is large.  Every year in the United States,  around 6,000 patients receive a new liver and more than 35,000 patients die of liver disease.

Searching for options

willenbring photo

Dr. Holger Willenbring

Dr. Holger Willenbring, a physician scientist at UCSF, is one of the CIRM-funded researchers pursuing a stem cell/regenerative medicine approach to discover a treatment for patients with severe liver disease.  There are significant challenges to treating liver disease including getting fully multi-functional hepatocytes and getting them to engraft and/or grow sufficiently to achieve adequate mass for necessary liver functions.

In previous CIRM–funded discovery research, Dr. Willenbring and his team showed that they could partially reprogram human fibroblasts (the most common cell found in connective tissue) and then turn them into immature hepatocytes.  (see our Spotlight on Liver Disease video from 2012 featuring Dr. Willenbring.) These immature hepatocytes, when transplanted into an immune-deficient mouse model of human liver failure, were shown to mature over time into hepatocytes that were comparable to normal human hepatocytes both in their gene expression and their function.

This was an important finding in that it suggested that the liver environment in a living animal (in vivo), rather than in a test tube (in vitro) in the laboratory, is important for full multi-functional maturation of hepatocytes.  The study also showed that these transplanted immature human hepatocytes could proliferate and improve the survival of this mouse model of chronic human liver disease.  But, even though this model was designed to emphasizes the growth of functional human hepatocytes, the number of cells generated was not great enough to suggest that transplantation could be avoided

A new approach

Dr. Willenbring and his team are now taking the novel approach of direct reprogramming inside the mouse.  With this approach, he seeks to avoid the challenge of low engraftment and proliferation of transplanted hepatocytes generated in the lab and transplanted. Instead, they aim to take advantage of the large number of myofibroblasts in the patient’s scarred liver by turning them directly into hepatocytes.

Recently, he and his team have shown proof-of principle that they can deliver genes to myofibroblasts and turn them into hepatocytes in a mouse. In addition these in vivo myofibroblasts-derived hepatocytes are multi-functional, and can multiply in number, and can even reverse fibrosis in a mouse with liver fibrosis.

From mice to men (women too)

Our latest round of funding for Dr. Willenbring has the goal of moving and extending these studies into human cells by improving the specificity and effectiveness of reprogramming of human myofibroblasts into hepatocytes inside the animal, rather than the lab.

He and his team will then conduct studies to test the therapeutic effectiveness and initial safety of this approach in preclinical models. The ultimate goal is to generate a potential therapy that could eventually provide hope for the 35,000 patients who die of liver disease each year in the US.

 

 

The Alpha Stem Cell Clinics: Innovation for Breakthrough Stem Cell Treatments

During this third week of the Month of CIRM, we are focusing on CIRM’s Infrastructure programs which are all focused on helping to accelerate stem cell treatments to patients with unmet medical needs.

So here is the question of the day: What is the world’s largest network of medical centers dedicated to providing stem cell treatments to patients?

The answer is the CIRM Alpha Stem Cell Clinics Network.

The CIRM Alpha Stem Cell Clinics Network consists of leading medical institutions throughout California.

The ASCC Network consists of six leading medical centers throughout California. In 2015, the Network was launched in southern California at the City of Hope, UC Irvine, UC Los Angeles, and UC San Diego. In September 2017, CIRM awarded funding to UC Davis and UC San Francisco to enable the Network to better serve patients throughout the state. Forty stem cell clinical trials have been conducted within the Network with hundreds of patients being treat for a variety of conditions, including:

  • Cancers of the blood, brain, lung and other sites
  • Organ diseases of the heart and kidney
  • Pediatric diseases
  • Traumatic injury to the brain and spine

A complete list of clinical trials may be found on our website.

The Alpha Clinics at UC Los Angeles and San Francisco are working collaboratively on breakthrough treatments for serious childhood diseases. This video highlights a CIRM-funded clinical trial at the UCLA Alpha Clinic that is designed to restore the immune system of patients with life-threatening immune deficiencies. A similar breakthrough treatment is also being used at the UCLA Alpha Clinic to treat sickle cell disease. A video describing this treatment is below.

Why do we need a specialized Network for stem cell clinical trials?

Stem cell treatments are unique in many ways. First, they consist of cells or cell products that frequently require specialized processing. For example, the breakthrough treatments for children, described above, requires the bone marrow to be genetically modified to correct defects. This “gene therapy” is performed in the Alpha Clinic laboratories, which are specifically designed to implement cutting edge gene therapy techniques on the patient’s stem cells.

Many of the cancer clinical trials also take the patient’s own cells and then process them in a laboratory. This processing is designed to enhance the patient’s ability to fight cancer using their own immune cells. Each Alpha Clinic has specialized laboratories to process cells, and the sites at City of Hope and UC Davis have world-class facilities for stem cell manufacturing. The City of Hope and Davis facilities produce high quality therapeutic products for commercial and academic clinical trial sponsors. Because of this ability, the Network has become a prime location internationally for clinical trials requiring processing and manufacturing services.

Another unique feature of the Network is its partnership with CIRM, whose mission is to accelerate stem cell treatments for patients with unmet medical needs. Often, this means developing treatments for rare diseases in which the patient population is comparatively small. For example, there about 40-100 immune deficient children born each year in the United States. We are funding clinical trials to help treat those children. The Network is also treating rare brain and blood cancers.

To find patients that may benefit from these treatments, the Network has developed the capacity to confidentially query over 20 million California patient records. If a good match is found, there is a procedure in place, that is reviewed by an ethics committee, where the patient’s doctor can be notified of the trial and pass that information to the patient. For patients that are interested in learning more, each Alpha Clinic has a Patient Care Coordinator with the job of coordinating the process of educating patients about the trial and assisting them if they choose to participate.

How Can I Learn More?

If you are a patient or a family member and would like to learn more about the CIRM Alpha Clinics, click here. There is contact information for each clinic so you can learn more about specific trials, or you can visit our Alpha Clinics Trials page for a complete list of trials ongoing in the Network.

If you are a patient or a trial sponsor interested in learning more about the services offered through our Alpha Clinics Network, visit our website.

Building California’s stem cell research community, from the ground up

For week three of the Month of CIRM, our topic is infrastructure. What is infrastructure? Read on for a big picture overview and then we’ll fill in the details over the course of the week.

When CIRM was created in 2001, our goal was to grow the stem cell research field in California. But to do that, we first had to build some actual buildings. Since then, our infrastructure programs have taken on many different forms, but all have been focused on a single mission – helping accelerate stem cell research to patients with unmet medical needs.
CIRM_Infrastucture-program-iconScreen Shot 2017-10-16 at 10.58.38 AM

In the early 2000’s, stem cell scientists faced a quandary. President George W. Bush had placed limits on how federal funds could be used for embryonic stem cell research. His policy allowed funding of research involving some existing embryonic stem cell lines, but banned research that developed or conducted research on new stem lines.

Many researchers felt the existing lines were not the best quality and could only use them in a limited capacity. But because they were dependent on the government to fund their work, had no alternative but to comply. Scientists who chose to use non-approved lines were unable to use their federally funded labs for stem cell work.

The creation of CIRM changed that. In 2008, CIRM launched its Major Facilities Grant Program. The program had two major goals:

1) To accommodate the growing numbers of stem cell researchers coming in California as a result of CIRM’s grants and funding.

2) To provide new research space that didn’t have to comply with the federal restrictions on stem cell research.

Over the next few years, the program invested $271million to help build 12 new research facilities around California from Sacramento to San Diego. The institutions used CIRM’s funding to leverage and attract an additional $543 million in funds from private donors and institutions to construct and furnish the buildings.

These world-class laboratories gave scientists the research space they needed to work with any kind of stem cell they wanted and develop new potential therapies. It also enabled the institutions to bring together under one roof, all the stem cell researchers, who previously had been scattered across each campus.

One other important benefit was the work these buildings provided for thousands of construction workers at a time of record unemployment in the industry. Here’s a video about the 12 facilities we helped build:

But building physical facilities was just our first foray into developing infrastructure. We were far from finished.

In the early days of stem cell research, many scientists used cells from different sources, created using different methods. This meant it was often hard to compare results from one study to another. So, in 2013 CIRM created an iPSC Repository, a kind of high tech stem cell bank. The repository collected tissue samples from people who have different diseases, turned those samples into high quality stem cell lines – the kind known as induced pluripotent stem cells (iPSC) – and then made those samples available to researchers around the world. This not only gave researchers a powerful resource to use in developing a deeper understanding of different diseases, but because the scientists were all using the same cell lines that meant their findings could be compared to each other.

That same year we also launched a plan to create a new, statewide network of clinics that specialize in using stem cells to treat patients. The goal of the Alpha Stem Cell Clinics Network is to support and accelerate clinical trials for programs funded by the agency, academic researchers or industry. We felt that because stem cell therapies are a completely new way of treating diseases and disorders, we needed a completely new way of delivering treatments in a safe and effective manner.

The network began with three clinics – UC San Diego, UCLA/UC Irvine, and City of Hope – but at our last Board meeting was expanded to five with the addition of UC Davis and UCSF Benioff Children’s Hospital Oakland. This network will help the clinics streamline challenging processes such as enrolling patients, managing regulatory procedures and sharing data and will speed the testing and distribution of experimental stem cell therapies. We will be posting a more detailed blog about how our Alpha Clinics are pushing innovative stem cell treatments tomorrow.

As the field advanced we knew that we had to find a new way to help researchers move their research out of the lab and into clinical trials where they could be tested in people. Many researchers were really good at the science, but had little experience in navigating the complex procedures needed to get the green light from the US Food and Drug Administration (FDA) to test their work in a clinical trial.

So, our Agency created the Translating (TC) and Accelerating Centers (AC). The idea was that the TC would help researchers do all the preclinical testing necessary to apply for permission from the FDA to start a clinical trial. Then the AC would help the researchers set up the trial and actually run it.

In the end, one company, Quintiles IMS, won both awards so we combined the two entities into one, The Stem Cell Center, a kind of one-stop-shopping home to help researchers move the most promising treatments into people.

That’s not the whole story of course – I didn’t even mention the Genomics Initiative – but it’s hard to cram 13 years of history into a short blog. And we’re not done yet. We are always looking for new ways to improve what we do and how we do it. We are a work in progress, and we are determined to make as much progress as possible in the years to come.

Saving Ronnie: Stem Cell & Gene Therapy for Fatal Bubble Baby Disease [Video]

During this second week of the Month of CIRM, we’ve been focusing on the people who are critical to accomplishing our mission to accelerate stem cell treatments to patients with unmet medical needs.

These folks include researchers, like Clive Svendsen and his team at Cedars-Sinai Medical Center who are working tirelessly to develop a stem cell therapy for ALS. My colleague Karen Ring, CIRM’s Social Media and Website Manager, featured Dr. Svendsen and his CIRM-funded clinical trial in Monday’s blog. And yesterday, in recognition of Stem Cell Awareness Day, Kevin McCormack, our Senior Director of Public Communications, blogged about the people within the stem cell community who have made, and continue to make, the day so special.

Today, in a new video, I highlight a brave young patient, Ronnie, and his parents who decided to participate in a CIRM-funded clinical trial run by St. Jude Children’s Research Hospital and UC San Francisco in an attempt to save Ronnie’s life from an often-fatal disease called severe combined immunodeficiency (SCID). This disorder, also known as bubble baby disease, leaves newborns without a functioning immune system which can turn a simple cold into a potentially deadly infection.

Watch this story’s happy ending in the video above.

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

CIRM Board Appoints Dr. Maria Millan as President and CEO

Dr. Maria Millan, President and CEO of CIRM, at the September Board meeting. (Todd Dubnicoff, CIRM)

Yesterday was a big day for CIRM. Our governing Board convened for its September ICOC meeting and appointed Dr. Maria Millan as our new President and CEO. Dr. Millan has been serving as the Interim President/CEO since July, replacing former President Dr. Randal Mills.

Dr. Millan has been at CIRM since 2012 and was instrumental in the development of CIRM’s infrastructure programs including the Alpha Stem Cell Clinics Network and the agency’s Strategic Plan, a five-year plan that lays out our agency’s goals through 2020. Previously, Dr. Millan was the Vice President of Therapeutics at CIRM, helping the agency fund 23 new clinical trials since the beginning of 2016.

The Board vote to appoint Dr. Millan as President and CEO was unanimous and enthusiastic. Chairman of the Board, Jonathan Thomas, shared the Board’s sentiments when he said,

“Dr. Millan is absolutely the right person for this position. Having seen Dr. Millan as the Interim CEO of CIRM for three months and how she has operated in that position, I am even more enthusiastic than I was before. I am grateful that we have someone of Maria’s caliber to lead our Agency.”

Dr. Millan has pursued a career devoted to helping patients. Before working at CIRM, she was an organ transplant surgeon and researcher and served as an Associate Professor of Surgery and Director of the Pediatric Organ Transplant Program at Stanford University. Dr. Millan was also the Vice President and Chief Medical Officer at StemCells, Inc.

In her permanent role as President, Dr. Millan is determined to keep CIRM on track to achieve the goals outlined in our strategic plan and to achieve its mission to accelerate treatments to patients with unmet needs. She commented in a CIRM press release,

“I joined the CIRM team because I wanted to make a difference in the lives of patients. They are the reason why CIRM exists and why we fund stem cell research. I am humbled and very honored to be CIRM’s President and look forward to further implementing our agency’s Strategic Plan in the coming years.”

The Board also voted to fund two new Alpha Stem Cell Clinics at UC Davis and UC San Francisco and five new clinical trials. Three of the clinical awards went to projects targeting cancer.

The City of Hope received $12.8 million to fund a Phase 1 trial targeting malignant gliomas (an aggressive brain cancer) using CAR-T cell therapy. Forty Seven Inc. received $5 million for a Phase 1b clinical trial treating acute myeloid leukemia. And Nohla Therapeutics received $6.9 million for a Phase 2 trial testing a hematopoietic stem cell and progenitor cell therapy to help patients suffering from neutropenia, a condition that leaves people susceptible to deadly infections, after receiving chemotherapy for acute myeloid leukemia.

The other two trials target diabetes and end stage kidney failure. ViaCyte, Inc. was awarded $20 million to fund a Phase 1/2 clinical trial to test its PEC-Direct islet cell replacement therapy for high-risk type 1 diabetes. Humacyte Inc. received $14.1 million to fund a Phase 3 trial that is comparing the performance of its acellular bioengineered vessel with the current standard of dialysis treatment for kidney disease patients.

The Board also awarded $5.2 million to Stanford Medicine for a late stage preclinical project that will use CRISPR gene editing technology to correct the sickle cell disease mutation in blood-forming stem cells to treat patients with sickle cell disease. This award was particularly well timed as September is Sickle Cell Awareness month.

The Stanford team, led by Dr. Matthew Porteus, hopes to complete the final experiments required for them to file an Investigational New Drug (IND) application with the FDA so they can be approved to start a clinical trial hopefully sometime in 2018. You can read more about Dr. Porteus’ work here and you can read our past blogs featuring Sickle Cell Awareness here and here.

With the Board’s vote yesterday, CIRM’s clinical trial count rises to 40 funded trials since its inception. 23 of these trials were funded after the launch of our Strategic Plan bringing us close to the half way point of funding 50 new clinical trials by 2020. With more “shots-on-goal” CIRM hopes to increase the chances that one of these trials will lead to an FDA-approved therapy for patients.


Related Links:

From trauma to treatment: a Patient Advocate’s journey from helping her son battle a deadly disease to helping others do the same

Everett SCID 1

For every clinical trial CIRM funds we create a Clinical Advisory Panel or CAP. The purpose of the CAP is to make recommendations and provide guidance and advice to both CIRM and the Project Team running the trial. It’s part of our commitment to doing everything we can to help make the trial a success and get therapies to the people who need them most, the patients.

Each CAP consists of three to five members, including a Patient Advocate, an external scientific expert, and a CIRM Science Officer.

Having a Patient Advocate on a CAP fills a critical need for insight from the patient’s perspective, helping shape the trial, making sure that it is being carried out in a way that has the patient at the center. A trial designed around the patient, and with the needs of the patient in mind, is much more likely to be successful in recruiting and retaining the patients it needs to see if the therapy works.

One of the clinical trials we are currently funding is focused on severe combined immunodeficiency disease, or SCID. It’s also known as “bubble baby” disease because children with SCID are born without a functioning immune system, so even a simple virus or infection can prove fatal. In the past some of these children were kept inside sterile plastic bubbles to protect them, hence the name “bubble baby.”

Everett SCID family

Anne Klein is the Patient Advocate on the CAP for the CIRM-funded SCID trial at UCSF and St. Jude Children’s Research Hospital. Her son Everett was born with SCID and participated in this clinical trial. We asked Anne to talk about her experience as the mother of a child with SCID, and being part of the research that could help cure children like Everett.

“When Everett was born his disease was detected through a newborn screening test. We found out he had SCID on a Wednesday, and by  Thursday we were at UCSF (University of California, San Francisco). It was very sudden and quite traumatic for the family, especially Alden (her older son). I was abruptly taken from Alden, who was just two and a half years old at the time, for two months. My husband, Brian Schmitt, had to immediately drop many responsibilities required to effectively run his small business. We weren’t prepared. It was really hard.”

(Everett had his first blood stem cell transplant when he was 7 weeks old – his mother Anne was the donor. It helped partially restore his immune system but it also resulted in some rare, severe complications as a result of his mother’s donor cells attacking his body. So when, three years later, the opportunity to get a stem cell therapy came along Anne and her husband, Brian, decided to say yes. After some initial problems following the transplant, Everett seems to be doing well and his immune system is the strongest it has ever been.)

“It’s been four years, a lot of ups and downs and a lot of trauma. But it feels like we have turned a corner. Everett can go outside now and play, and we’re hanging out more socially because we no longer have to be so concerned about him being exposed to germs or viruses.

His doctor has approved him to go to daycare, which is amazing. So, Everett is emerging into the “normal” world for the first time. It’s nerve wracking for us, but it’s also a relief.”

Everett SCID in hospital

How Anne came to be on the CAP

“Dr. Cowan from UCSF and Dr. Malech from the NIH (National Institutes of Health) reached out to me and asked me about it a few months ago. I immediately wanted to be part of the group because, obviously, it is something I am passionate about. Knowing families with SCID and what they go through, and what we went through, I will do everything I can to help make this treatment more available to as many people as need it.

I can provide insight on what it’s like to have SCID, from the patient perspective; the traumas you go through. I can help the doctors and researchers understand how the medical community can be perceived by SCID families, how appreciative we are of the medical staff and the amazing things they do for us.

I am connected to other families, both within and outside of the US, affected by this disease so I can help get the word out about this treatment and answer questions for families who want to know. It’s incredibly therapeutic to be part of this wider community, to be able to help others who have been diagnosed more recently.”

The CAP Team

“They were incredibly nice and when I did speak they were very supportive and seemed genuinely interested in getting feedback from me. I felt very comfortable. I felt they were appreciative of the patient perspective.

I think when you are a research scientist in the lab, it’s easy to miss the perspective of someone who is actually experiencing the disease you are trying to fix.

At the NIH, where Everett had his therapy, the stem cell lab people work so hard to process the gene corrected cells and get them to the patient in time. I looked through the window into the hall when Everett was getting his therapy and the lab staff were outside, in their lab coats, watching him getting his new cells infused. They wanted to see the recipient of the life-saving treatment that they prepared.

It is amazing to see the process that the doctors go through to get treatments approved. I like being on the CAP and learning about the science behind it and I think if this is successful in treating others, then that would be the best reward.”

The future:

“We still have to fly back to the NIH, in Bethesda, MD, every three months for checkups. We’ll be doing this for 15 years, until Everett is 18. It will be less frequent as Everett gets older but this kind of treatment is so new that it’s still important to do this kind of follow-up. In between those trips we go to UCSF every month, and Kaiser every 1-3 weeks, sometimes more.

I think the idea of being “cured”, when you have been through this, is a difficult thing to think about. It’s not a word I use lightly as it’s a very weighted term. We have been given the “all clear” before, only to be dealt setbacks later. Once he’s in school and has successfully conquered some normal childhood illnesses, both Brian and I will be able to relax more.

One of Everett’s many doctors once shared with me that, in the past, he sometimes had to tell parents of very sick children with SCID that there was nothing else they could do to help them. So now to have a potential treatment like this, he was so excited about a stem cell therapy showing such promise.

One thing we think about Everett and Alden, is that they are both so young and have been through so much already. I’m hoping that they can forget all this and have a chance to grow up and lead a normal life.”

Stem cell stories that caught our eye: bubble baby therapy a go in UK, in-utero stem cell trial and novel heart disease target

There were lots of CIRM mentions in the news this week. Here are two brief recaps written by Karen Ring to get you up to speed. A third story by Todd Dubnicoff summarizes an promising finding related to heart disease by researchers in Singapore.  

CIRM-funded “bubble baby” disease therapy gets special designation by UK.
Orchard Therapeutics, a company based in the UK and the US, is developing a stem cell-based gene therapy called OTL-101 to treat a primary immune disease called adenosine-deaminase deficient severe combined immunodeficiency (ADA-SCID), also known as “bubble baby disease”. CIRM is funding a Phase 1/2 clinical trial led by Don Kohn of UCLA in collaboration with Orchard and the University College in London.

In July, the US Food and Drug Administration (FDA) awarded OTL-101 Rare Pediatric Disease Designation (read more about it here), which makes the therapy eligible for priority review by the FDA, and could give it a faster route to being made more widely available to children in need.

On Tuesday, Orchard announced further good news that OTL-101 received “Promising Innovative Medicine Designation” by the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA). In a news release, the company explained how this designation bodes well for advancing OTL-101 from clinical trials into patients,

“The designation as Promising Innovative Medicine is the first step of a two-step process under which OTL-101 can benefit from the Early Access to Medicine Scheme (“EAMS”). Nicolas Koebel, Senior Vice President for Business Operations at Orchard, added: “With this PIM designation we can potentially make OTL-101 available to UK patients sooner under the Early Access to Medicine Scheme”.

CIRM funded UCSF clinical trial mentioned in SF Business Times
Ron Leuty, reporter at the San Francisco Business Times, published an article about a CIRM-funded trial out of UCSF that is targeting a rare genetic blood disease called alpha thalassemia major, describing it as, “The world’s first in-utero blood stem cell transplant, soon to be performed at the University of California, San Francisco, could point the way toward pre-birth cures for a range of blood diseases, such as sickle cell disease.”

Alpha Thalassemia affects the ability of red blood cells to carry oxygen because of a reduction in a protein called hemoglobin. The UCSF trial, spearheaded by UCSF Pediatric surgeon Dr. Tippi MacKenzie, is hoping to use stem cells from the mother to treat babies in the womb to give them a better chance at surviving after birth.

In an interview with Leuty, Tippi explained,

“Our goal is to put in enough cells so the baby won’t need another transplant. But even if we fall short, if we can just establish 1 percent maternal cells circulating in the child, it will establish tolerance and then they can get the booster transplant.”

She also emphasized the key role that CIRM funded played in the development and launch of this clinical trial.

“CIRM is about more than funding for studies, MacKenzie said. Agency staff has provided advice about how to translate animal studies into work in humans, she said, as well as hiring an FDA consultant, writing an investigational new drug application and setting up a clinical protocol.”

“I’m a clinician, but running a clinical trial is different,” MacKenzie said. “CIRM’s been incredibly helpful in helping me navigate that.”

Heart, heal thyself: the story of Singheart
When you cut your finger or scrape a knee, a scab forms, allowing the skin underneath to regenerate and repair itself. The heart is not so lucky – it has very limited self-healing abilities. Instead, heart muscle cells damaged after a heart attack form scar tissue, making each heart beat less efficient. This condition can lead to chronic heart disease, the number one killer of both men and women in the US.

A mouse heart cell with 2 nuclei (blue) and Singheart RNA labelled by red fluorescent dyes.
Credit: A*STAR’s Genome Institute of Singapore

Research has shown that newborn mice retain the ability to completely regenerate and repair injuries to the heart because their heart muscle cells, or cardiomyocytes, are still able to divide and replenish damaged cells. But by adulthood, the mouse cardiomyocytes lose the ability to stimulate the necessary cell division processes. A research team in Singapore wondered what was preventing cardiomyocytes cell division in adult mice and if there was some way to lift that block.

This week in Nature Communications, they describe the identification of a molecule they call Singheart that may be the answer to their questions. Using tools that allow the analysis of gene activity in single cells revealed that a rare population of diseased cardiomyocytes are able to crank up genes related to cell division. And further analysis showed Singheart, a specialized genetic molecule called a long non-coding RNA, played a role in blocking this cell division gene.

As lead author Dr. Roger Foo, a principal investigator at Genome Institute of Singapore (GIS) and the National University Health System (NUHS), explained in a press release, these findings may lead to new self-healing strategies for heart disease,

“There has always been a suspicion that the heart holds the key to its own healing, regenerative and repair capability. But that ability seems to become blocked as soon as the heart is past its developmental stage. Our findings point to this potential block that when lifted, may allow the heart to heal itself.”

Stem cell stories that caught our eye: new baldness treatments?, novel lung stem cells, and giraffe stem cells

Novel immune system/stem cell interaction may lead to better treatments for baldness. When one thinks of the immune system it’s usually in terms of the body’s ability to fight off a bad cold or flu virus. But a team of UCSF researchers this week report in Cell that a particular cell of the immune system is key to instructing stem cells to maintain hair growth. Their results suggest that the loss of these immune cells, called regulatory T cells (Tregs for short), may be the cause of baldness seen in alopecia areata, a common autoimmune disorder and may even play a role in male pattern baldness.

Alopecia, a common autoimmune disorder that causes baldness. Image: Shutterstock

While most cells of the immune system recognize and kill foreign or dysfunctional cells in our bodies, Tregs act to subdue those cells to avoid collateral damage to perfectly healthy cells. If Tregs become impaired, it can lead to autoimmune disorders in which the body attacks itself.

The UCSF team had previously shown that Tregs allow microorganisms that are beneficial to skin health in mice to avoid the grasp of the immune system. In follow up studies they intended to examine what happens to skin health when Treg cells were inhibited in the skin of the mice. The procedure required shaving away small patches of hair to allow observation of the skin. Over the course of the experiment, the scientists notice something very curious. Team lead Dr. Michael Rosenblum recalled what they saw in a UCSF press release:

“We quickly noticed that the shaved patches of hair never grew back, and we thought, ‘Hmm, now that’s interesting. We realized we had to delve into this further.”

That delving showed that Tregs are located next to hair follicle stem cells. And during the hair growth, the Tregs grow in number and surround the stem cells. Further examination, found that Tregs trigger the stem cells through direct cell to cell interactions. These mechanisms are different than those used for their immune system-inhibiting function.

With these new insights, Dr. Rosenblum hopes this new-found role for Tregs in hair growth may lead to better treatments for Alopecia, one of the most common forms of autoimmune disease.

Novel lung stem cells bring new insights into poorly understood chronic lung disease. Pulmonary fibrosis is a chronic lung disease that’s characterized by scarring and changes in the structure of tiny blood vessels, or microvessels, within lungs. This so-called “remodeling” of lung tissue hampers the transfer of oxygen from the lung to the blood leading to dangerous symptoms like shortness of breath. Unfortunately, the cause of most cases of pulmonary fibrosis is not understood.

This week, Vanderbilt University Medical Center researchers report in the Journal of Clinical Investigation the identification of a new type of lung stem cell that may play a role in lung remodeling.

Susan Majka and Christa Gaskill, and colleagues are studying certain lung stem cells that likely contribute to the pathobiology of chronic lung diseases.  Photo by: Susan Urmy

Up until now, the cells that make up the microvessels were thought to contribute to the detrimental changes to lung tissue in pulmonary fibrosis or other chronic lung diseases. But the Vanderbilt team wasn’t convinced since these microvessel cells were already fully matured and wouldn’t have the ability to carry out the lung remodeling functions.

They had previously isolated stem cells from both mouse and human lung tissue located near microvessels. In this study, they tracked these mesenchymal progenitor cells (MPCs) in normal and disease inducing scenarios. The team’s leader, Dr. Susan Majka, summarized the results of this part of the study in a press release:

“When these cells are abnormal, animals develop vasculopathy — a loss of structure in the microvessels and subsequently the lung. They lose the surfaces for gas exchange.”

The team went on to find differences in gene activity in MPCs from healthy versus diseased lungs. They hope to exploit these differences to identify molecules that would provide early warnings of the disease. Dr. Majka explains the importance of these “biomarkers”:

“With pulmonary vascular diseases, by the time a patient has symptoms, there’s already major damage to the microvasculature. Using new biomarkers to detect the disease before symptoms arise would allow for earlier treatment, which could be effective at decreasing progression or even reversing the disease process.”

The happy stem cell story of Mahali the giraffe. We leave you this week with a feel-good story about Mahali, a 14-year old giraffe at the Cheyenne Mountain Zoo in Colorado. Mahali had suffered from chronic arthritis in his front left leg. As a result, he could not move well and was kept isolated from his herd.

Giraffes at Cheyenne Mountain Zoo. Photo: Denver Post

The zoo’s head veterinarian, Dr. Liza Dadone, decided to try a stem cell therapy procedure to bring Mahali some relief and a better quality of life. It’s the first time such a treatment would be performed on a giraffe. With the help of doctors at Colorado State University’s James L. Voss Veterinary Teaching Hospital, 100 million stem cells grown from Mahali’s blood were injected into his arthritic leg.

Before treatment, thermograph shows inflammation (red/yellow) in Mahali’s left front foot (seen at far right of each image); after treatment inflammation resolved (blue/green). Photos: Cheyenne Mountain Zoo

In a written statement to the Colorado Gazette, Dr. Dadone summarized the positive outcome:

“Prior to the procedure, he was favoring his left front leg and would lift that foot off the ground almost once per minute. Since then, Mahali is no longer constantly lifting his left front leg off the ground and has resumed cooperating for hoof care. A few weeks ago, he returned to life with his herd, including yard access. On the thermogram, the marked inflammation up the leg has mostly resolved.”

Now, Dr. Dadone made sure to state that other treatments and medicine were given to Mahali in addition to the stem cell therapy. So, it’s not totally clear to what extent the stem cells contributed to Mahali’s recovery. Maybe future patients will receive stem cells alone to be sure. But for now, we’re just happy for Mahali’s new lease on life.