Gene therapy gives patient a cure and a new lease on life

Brenden Whittaker (left), of Ohio, is a patient born with a rare genetic immune disease who was treated at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in a CIRM funded gene therapy trial. Dr. David Williams (on right) is Brenden’s treating physician.
Photo courtesy of Rose Lincoln – Harvard Staff Photographer

Pursuing an education can be quite the challenge in itself without the added pressure of external factors. For Brenden Whittaker, a 25 year old from Ohio, the constant trips to the hospital and debilitating nature of an inherited genetic disease made this goal particularly challenging and, for most of his life, out of sight.

Brenden was born with chronic granulomatous disease (CGD), a rare genetic disorder that affects the proper function of neutrophils, a type of white blood cell that is an essential part of the body’s immune system. This leads to recurring bacterial and fungal infections and the formation of granulomas, which are clumps of infected tissue that arise as the body attempts to isolate infections it cannot combat. People with CGD are often hospitalized routinely and the granulomas themselves can obstruct digestive pathways and other pathways in the body. Antibiotics are used in an attempt to prevent infections from occurring, but eventually patients stop responding to them. One in two people with CGD do not live past the age of 40.

In Brenden’s case, when the antibiotics he relied on started failing, the doctors had to resort to surgery to cut out an infected lobe of his liver and half his right lung. Although the surgery was successful, it would only be a matter of time before a vital organ was infected and surgery would no longer be an option.

This ultimately lead to Brenden becoming the first patient in a CGD gene therapy trial at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.  The trial, lead by UCLA’s Dr. Don Kohn thanks to a CIRM grant, combats the disease by correcting the dysfunctional gene inside a patient’s blood stem cells. The patient’s corrected blood stem cells are then reintroduced, allowing the body to produce properly functioning neutrophils, rebooting the immune system.

It’s been a little over three years since Brenden received this treatment in late 2015, and the results have been remarkable. Dr. David Williams, Brenden’s treating physician, expected Brenden’s body to produce at least 10 percent of the functional neutrophils, enough so that Brenden’s immune system would provide protection similar to somebody without CGD. The results were over 50 percent, greatly exceeding expectations.

Brenden Whittaker mowing the lawn in the backyard of his home in Columbus, Ohio. He is able to do many more things without the fear of infection since participating in the trial. Photo courtesy of Colin McGuire

In an article published by The Harvard Gazette, Becky Whittaker, Brendan’s mother, is quoted as saying, ““Each day that he’s free of infection, he’s able to go to class, he’s able to work at his part-time job, he’s able to mess around playing with the dog or hanging out with friends…[this] is a day I truly don’t believe he would have had beyond 2015 had something not been done.”

In addition to the changes to his immune system, the gene therapy has reinvigorated Brenden’s drive for the future. Living with CGD had caused Brenden to miss out on much of his schooling throughout the years, having to take constant pauses from his academics at a community college. Now, Brenden aims to graduate with an associate’s degree in health sciences in the spring and transfer to Ohio State in the fall for a bachelor’s degree program. In addition to this, Brenden now has dreams of attending medical school.

In The Harvard Gazette article, Brenden elaborates on why he wants to go to medical school saying, ” Just being the patient for so long, I want to give back. There are so many people who’ve been there for me — doctors, nurses who’ve been there for me [and] helped me for so long.”

In a press release dated February 25, 2019, Orchard Therapeutics, a biopharmaceutical company that is continuing the aforementioned approach for CGD, announced that six patients treated have shown adequate neutrophil function 12 months post treatment. Furthermore, these six patients no longer receive antibiotics related to CGD. Orchard Therapeutics also announced that they are in the process of designing a registrational trial for CGD.

Midwest universities are making important tools to advance stem cell research

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iPSCs are not just pretty, they’re also pretty remarkable

Two Midwest universities are making headlines for their contributions to stem cell research. Both are developing important tools to advance this field of study, but in two unique ways.

Scientists at the University of Michigan (UM), have compiled an impressive repository of disease-specific stem cell lines. Cell lines are crucial tools for scientists to study the mechanics of different diseases and allows them to do so without animal models. While animal models have important benefits, such as the ability to study a disease within the context of a living mammal, insights gained from such models can be difficult to translate to humans and many diseases do not even have good models to use.

The stem cell lines generated at the Reproductive Sciences Program at UM, are thanks to numerous individuals who donated extra embryos they did not use for in vitro fertilization (IVF). Researchers at UM then screened these embryos for abnormalities associated with different types of disease and generated some 36 different stem cell lines. These have been donated to the National Institute of Health’s (NIH) Human Embryonic Stem Cell Registry, and include cell lines for diseases such as cystic fibrosis, Huntington’s Disease and hemophilia.

Using one such cell line, Dr. Peter Todd at UM, found that the genetic abnormality associated with Fragile X Syndrome, a genetic mutation that results in developmental delays and learning disabilities, can be corrected by using a novel biological tool. Because Fragile X Syndrome does not have a good animal model, this stem cell line was critical for improving our understanding of this disease.

In the next state over, at the University of Wisconsin-Madison (UWM), researchers are doing similar work but using induced pluripotent stem cells (iPSCs) for their work.

The Human Stem Cell Gene Editing Service has proved to be an important resource in expediting research projects across campus. They use CRISPR-Cas9 technology (an efficient method to mutate or edit the DNA of any organism), to generate human stem cell lines that contain disease specific mutations. Researchers use these cell lines to determine how the mutation affects cells and/or how to correct the cellular abnormality the mutation causes. Unlike the work at UM, these stem cell lines are derived from iPSCs  which can be generated from easy to obtain human samples, such as skin cells.

The gene editing services at UWM have already proved to be so popular in their short existence that they are considering expanding to be able to accommodate off-campus requests. This highlights the extent to which both CRISPR technology and stem cell research are being used to answer important scientific questions to advance our understanding of disease.

CIRM also created an iPSC bank that researchers can use to study different diseases. The  Induced Pluripotent Stem Cell (iPSC) Repository is  the largest repository of its kind in the world and is used by researchers across the globe.

The iPSC Repository was created by CIRM to house a collection of stem cells from thousands of individuals, some healthy, but some with diseases such as heart, lung or liver disease, or disorders such as autism. The goal is for scientists to use these cells to better understand diseases and develop and test new therapies to combat them. This provides an unprecedented opportunity to study the cell types from patients that are affected in disease, but for which cells cannot otherwise be easily obtained in large quantities.

CCSF’s CIRM Bridges scholars: the future of stem cell research is in good hands

In need of an extra dose of inspiration? You might read a great book or listen to that podcast your friend recommended. You might even take a stroll along the beach. But I can do you one better: go to a conference poster session where young stem cell scientists describe their research.

That’s what I did last week at the City College of San Francisco’s (CCSF) Bioscience Symposium held at UC San Francisco’s Genentech Hall. It’s a day-long conference that showcases the work of CCSF Bioscience interns and gives them a chance to present the results of their research projects, network with their peers and researchers, hear panelists talk about careers in biotechnology and participate in practice job interviews.

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CCSF’s CIRM Bridges Scholars (clockwise from top left): Vanessa Lynn Herrara, Viktoriia Volobuieva, Christopher Nosworthy and Sofiana E. Hamama.

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CCSF’s CIRM Bridges Scholars (clockwise from top left): Seema Niddapu, Mark Koontz, Karolina Kaminska and Iris Avellano

Eight of the dozens of students in attendance at the Symposium are part of the CIRM-funded Bridges Stem Cell Internship program at CCSF. It’s one of 14 CIRM Bridges programs throughout the state that provides paid stem cell research internships to students at universities and colleges that don’t have major stem cell research programs. Each Bridges internship includes thorough hands-on training and education in stem cell research, and direct patient engagement and outreach activities that engage California’s diverse communities.

In the CCSF Bridges Program, directed by Dr. Carin Zimmerman, the students do a 9-month paid internship in top notch labs at UCSF, the Gladstone Institutes and Blood System Research Institute. As I walked from poster to poster and chatted with each Bridges scholar, their excitement and enthusiasm for carrying out stem cell research was plain to see. It left me with the feeling that the future of stem cell research is in good hands and, as I walked into the CIRM office the next day, I felt re-energized to tackle the Agency’s mission to accelerate stem cell treatment for patients with unmet medical needs. But don’t take my word for it, listen to the enthusiastic perspectives of Bridges scholars Mark Koontz and Iris Avellano in this short video.

Meet the high school student who moonlights as a neuroscientist

As part of our CIRM scholar blog series, we’re featuring the research and career accomplishments of CIRM funded students. Today, you’ll read about one of our former SPARK high school students.


Emma Friedenberg and former CIRM SPARK Director Karen Ring at the 2017 SPARK Conference.

Emma Friedenberg is a high school senior at Campbell Hall in North Hollywood, California. She’s also an up-and-coming neuroscientist who has her sights set on unraveling the complexities of the brain and discovering cures for degenerative brain diseases. Emma spent the summer of 2017 studying Huntington’s disease in the lab of Dr. Virginia Mattis at the Cedars-Sinai Medical Center. Her internship was possible because of the CIRM SPARK high school educational program which gives California students the opportunity to do stem cell research for a summer.

Below is an interview with Emma about her SPARK experience and how the program is helping her pursue her passions for research and medicine.

Q: How did you learn about the CIRM SPARK program and why did you want to apply?

I’ve been a clinical volunteer at Cedars-Sinai Medical Center for two years in the Intensive Care Unit and the Neurology and Spine Unit. I was submitting my application to return as a volunteer when I explored Cedars-Sinai’s Outreach website page and found the CIRM SPARK program. I knew immediately it was a perfect fit. I plan on studying neuroscience in college with an intention of obtaining my medical degree and becoming a surgeon. The CIRM SPARK program at Cedars within the Board of Governor’s Regenerative Medicine Institute had an option to be involved specifically in the Brain Program. In Dr. Virginia Mattis’ lab, I studied translational stem cell therapies for neurodegenerative diseases, in particular Huntington’s Disease. As Cedars-Sinai calls it, a “bench to bedside” approach is an unparalleled and invaluable experience and huge advantage in science.

Q: What was your SPARK research project?

At Cedars-Sinai, I was mentored by Dr. Virginia Mattis in her stem cell lab. The Mattis Lab researches stem cell therapies for Huntington’s disease (HD), a neurodegenerative brain disease. HD is caused by a loss of neurons, specifically medium spiny neurons in the striatum of Huntington’s patients. We used induced pluripotent stem cells to model HD in a petri dish to study the development of the disease and to create medium spiny neurons that could one day be transplanted into Huntington’s patients to replace lost and damaged cells.

Medium spiny neurons made from Huntington’s disease patient induced pluripotent stem cells. (Image credit: Mattis Lab, Cedars Sinai)

My primary research in the Mattis Lab was experimenting on our cell line to find the most time and cost-effective procedure to produce large populations of medium spiny neurons, because current methods are expensive and largely inefficient. However, my internship was not limited to the laboratory. I spent a significant amount of time shadowing doctors in the ALS Clinic.

Q: What was your experience in the CIRM SPARK program like?

In one word, the CIRM SPARK program was incredible –a one of a kind opportunity. The sciences are my personal passion and the cornerstone of my academic pursuits. The CIRM SPARK program has bolstered my scientific knowledge and provided practical experience in a real-world laboratory environment. A career in medicine is a significant commitment, and I’m confident the CIRM SPARK program was a beneficial start to obtaining my goals.

Cedars-Sinai SPARK students celebrating the completion of their 2017 internships.

Q: What do you value most about your SPARK experience?

It was wonderful to be part of a program which understood collaboration and offered a plethora of learning opportunities outside of the wet lab. What I will keep with me is not only techniques of immunocytochemistry and microscopy, but also the advice and encouragement from accomplished scientists like Clive Svendsen and my mentor Virginia Mattis.

Q: What are your future goals?

I plan on studying neuroscience in college with an intention of obtaining my medical degree and becoming a surgeon.

Q: Who is your scientific idol and why?

I recently read Dr. Eric Kandel’s book, The Age of Insight: The Quest to Understand the Unconscious in Art, Mind, and Brain, from Vienna 1900 to the Present. Dr. Kandel is a neuroscientist and a Professor at Columbia University. He received the Nobel Prize for his work in memory storage using Aplysia, a type of sea slug. His book examines how the human brain responds to art. What I find so inspiring about his book is his interdisciplinary approach to science, a combination of neuroscience, psychoanalysis, biology, and art. The human brain is so complicated that it can be studied from numerous perspectives, from biology to chemistry to electrophysiology. It is not until we can begin to merge these understandings that we will begin to unlock the secrets of the brain. Dr. Kandel is not only a scientist, but an intellectual.

Q: What is your favorite thing about being a scientist?

For centuries, the human brain was an anomaly, unexplainable by science. With 100 billion neurons and 100 trillion connections, the brain is the most complex network in the universe. How the brain functions as an information-processing organ and regulates emotion, behavior, and cognition as well as basic body functions like breathing remains a mystery. In recent years, there has been significant progress in brain research. Scientists are on the brink of major breakthroughs, but there is significant work to do particularly on neurological brain disorders. Being a scientist means living on the cutting-edge of human innovation. I enjoy being able to both ask and answer questions that will benefit humankind.


Related Links:

The Story of a South African Bubble Boy and a Gene Therapy That Gave Him His Life Back

Ayaan Isaacs, health24

Ayaan Isaacs was born in South Africa on March 4th, 2016 as a seemingly healthy baby. But only a few days in to life, he contracted a life-threatening liver infection. He thankfully survived, only to have the doctors discover a few weeks later that he had something much more troubling – a rare disease that left him without a functioning immune system.

Ayaan was diagnosed with X-linked severe combined immunodeficiency (SCID), which is often referred to as ‘bubble baby’ disease because patients are extremely susceptible to infection and must live in sterile environments. SCID patients can be cured with a blood stem cell transplant if they have a genetically matched donor. Unfortunately for Ayaan, only a partially matched donor was available, which doesn’t guarantee a positive outcome.

Ayaan’s parents were desperate for an alternative treatment to save Ayaan’s life. It was at this point that they learned about a clinical trial at St. Jude Children’s Research hospital in Memphis, Tennessee. The trial is treating SCID patients with a stem cell gene therapy that aims to give them a new functioning immune system. The therapy involves extracting the patient’s blood-forming stem cells and genetically correcting the mutation that causes SCID. The corrected blood stem cells are then transplanted back into the patient where they rebuild a healthy immune system.

Ayaan was able to enroll in the trial, and he was the first child in Africa to receive this life-saving gene therapy treatment. Ayaan’s journey with bubble boy disease was featured by South Africa’s health24 earlier this year. In the article, his mom Shamma Sheik talked about the hope that this gene therapy treatment brought to their family.

“No child should have to die just because they are unable to find a donor. Gene therapy offered Ayaan a chance at life that he ordinarily would not have had. I was fortunate to have found an alternative therapy that is working and already showing remarkable results. We are mindful that this is still an experimental treatment and there are complications that can arise; however, I am very optimistic that he will return to South Africa with a functioning immune system.”

Carte Blanche, an investigative journalism program in South Africa, did a feature video of Ayaan in February. Although the video is no longer available on their website, it did reveal that four months after Ayaan’s treatment, his condition started to improve suggesting that the treatment was potentially working.

We’ve written previously about another young boy named Ronnie who was diagnosed with X-linked SCID days after he was born. Ronnie also received the St. Jude stem cell gene therapy in a CIRM-funded clinical trial at the UCSF Benioff Children’s Hospital. Ronnie was treated when he was six months old and just celebrated his first birthday as a healthy, vibrant kid thanks to this trial. You can hear more about Ronnie’s moving story from his dad, Pawash Priyank, in the video below.

Our hope is that powerful stories like Ayaan’s and Ronnie’s will raise awareness about SCID and the promising potential of stem cell gene therapies to cure patients of this life-threatening immune disease.

Ronnie and his parents celebrating his 1st birthday. (Photo courtesy of Pawash Priyank)


Related Links:

Throwback Thursday: Progress towards a cure for HIV/AIDS

Welcome 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 research and clinical trials that are aimed at developing stem cell-based treatments for HIV/AIDS.

 Tomorrow, December 1st, is World AIDS Day. In honor of the 34 million people worldwide who are currently living with HIV, we’re dedicating our latest #ThrowbackThursday blog to the stem cell research and clinical trials our Agency is funding for HIV/AIDS.

world_logo3To jog your memory, HIV is a virus that hijacks your immune cells. If left untreated, HIV can lead to AIDS – a condition where your immune system is compromised and cannot defend your body against infection and diseases like cancer. If you want to read more background about HIV/AIDs, check out our disease fact sheet.

Stem Cell Advancements in HIV/AIDS
While patients can now manage HIV/AIDS by taking antiretroviral therapies (called HAART), these treatments only slow the progression of the disease. There is no effective cure for HIV/AIDS, making it a significant unmet medical need in the patient community.

CIRM is funding early stage research and clinical stage research projects that are developing cell based therapies to treat and hopefully one day cure people of HIV. So far, our Agency has awarded 17 grants totalling $72.9 million in funding to HIV/AIDS research. Below is a brief description of four of these exciting projects:

Discovery Stage Research
Dr. David Baltimore at the California Institute of Technology is developing an innovative stem cell-based immunotherapy that would prevent HIV infection in specific patient populations. He recently received a CIRM Quest award, (a funding initiative in our Discovery Stage Research Program) to pursue this research.

CIRM science officer, Dr. Ross Okamura, oversees Baltimore’s CIRM grant. He explained how the Baltimore team is genetically modifying the blood stem cells of patients so that they develop into immune cells (called T cells) that specifically recognize and target the HIV virus.

Ross_IDCard

Ross Okamura, PhD

“The approach Dr. Baltimore is taking in his CIRM Discovery Quest award is to engineer human immune stem cells to suppress HIV infection.  He is providing his engineered cells with T cell protein receptors that specifically target HIV and then exploring if he can reduce the viral load of HIV (the amount of virus in a specific volume) in an animal model of the human immune system. If successful, the approach could provide life-long protection from HIV infection.”

While Baltimore’s team is currently testing this strategy in mice, if all goes well, their goal is to translate this strategy into a preventative HIV therapy for people.

Clinical Trials
CIRM is currently funding three clinical trials focused on HIV/AIDS led by teams at Calimmune, City of Hope/Sangamo Biosciences and UC Davis. Rather than spelling out the details of each trial, I’ll refer you to our new Clinical Trial Dashboard (a screenshot of the dashboard is below) and to our new Blood & Immune Disorders clinical trial infographic we released in October.

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As you can see from these projects, CIRM is committed to funding cutting edge research in HIV/AIDS. We hope that in the next few years, some of these projects will bear fruit and help advance stem cell-based therapies to patients suffering from this disease.

I’ll leave you with a few links to other #WorldAIDSDay relevant blogs from our Stem Cellar archive and our videos that are worth checking out.

 

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.

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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.

Stanford scientists are growing brain stem cells in bulk using 3D hydrogels

This blog is the final installment in our #MonthofCIRM series. Be sure to check out our other blogs highlighting important advances in CIRM-funded research and initiatives.

Neural stem cells from the brain have promising potential as cell-based therapies for treating neurological disorders such as Alzheimer’s disease, Parkinson’s, and spinal cord injury. A limiting factor preventing these brain stem cells from reaching the clinic is quantity. Scientists have a difficult time growing large populations of brain stem cells in an efficient, cost-effective manner while also maintaining the cells in a stem cell state (a condition referred to as “stemness”).

CIRM-funded scientists from Stanford University are working on a solution to this problem. Dr. Sarah Heilshorn, an associate professor of Materials Science and Engineering at Stanford, and her team are engineering 3D hydrogel technologies to make it easier and cheaper to expand high-quality neural stem cells (NSCs) for clinical applications. Their research was published yesterday in the journal Nature Materials.

Stem Cells in 3D

Similar to how moviegoers prefer to watch the latest Star Wars installment in 3D, compared to the regular screen, scientists are turning to 3D materials called hydrogels to grow large numbers of stem cells. Such an environment offers more space for the stem cells to proliferate and expand their numbers while keeping them happy in their stem cell state.

To find the ideal conditions to grow NSCs in 3D, Heilshorn’s team tested two important properties of hydrogels: stiffness and degradability (or how easy it is to remodel the structure of the hydrogel material). They designed a range of hydrogels, made from proteins with elastic qualities, that varied in these two properties. Interestingly, they found that the stiffness of the material did not have a profound effect on the “stemness” of NSCs. This result contrasts with other types of adult stem cells like muscle stem cells, which quickly differentiate into mature muscle cells when exposed to stiffer materials.

On the other hand, the researchers found that it was crucial for the NSCs to be able to remodel their 3D environment. NSCs maintained their stemness by secreting enzymes that broke down and rearranged the molecules in the hydrogels. If this enzymatic activity was blocked, or if the cells were grown in hydrogels that couldn’t be remodeled easily, NSCs lost their stemness and stopped proliferating. The team tested two other hydrogel materials and found the same results. As long as the NSCs were in a 3D environment they could remodel, they were able to maintain their stemness.

NSCs maintain their stemness in hydrogels that can be remodeled easily. Nestin (green) and Sox2 (red) are markers that indicate “high-quality” NSCs. (Image courtesy of Chris Madl, Stanford)

Caption: NSCs maintain their stemness in hydrogels that can be remodeled easily. Nestin (green) and Sox2 (red) are markers that indicate “high-quality” NSCs. (Images courtesy of Chris Madl)

Christopher Madl, a PhD student in the Heilshorn lab and the first author on the study, explained how remodeling their 3D environment allows NSCs to grow robustly in an interview with the Stem Cellar:

Chris Madl

“In this study, we identified that the ability of the neural stem cells to dynamically remodel the material was critical to maintaining the correct stem cell state. Being able to remodel (or rearrange) the material permitted the cells to contact each other.  This cell-cell contact is responsible for maintaining signals that allow the stem cells to stay in a stem-like state. Our findings allow expansion of neural stem cells from relatively low-density cultures (aiding scale-up) without the use of expensive chemicals that would otherwise be required to maintain the correct stem cell behavior (potentially decreasing cost).”

To 3D and Beyond

When asked what’s next on the research horizon, Heilshorn said two things:

Sarah Heilshorn

“First, we want to see if other stem cell types – for example, pluripotent stem cells – are also sensitive to the “remodel-ability” of materials. Second, we plan to use our discovery to create a low-cost, reproducible material for efficient expansion of stem cells for clinical applications. In particular, we’d like to explore the use of a single material platform that is injectable, so that the same material could be used to expand the stem cells and then transplant them.”

Heilshorn is planning to apply the latter idea to advance another study that her team is currently working on. The research, which is funded by a CIRM Tools and Technologies grant, aims to develop injectable hydrogels containing NSCs derived from human induced pluripotent stem cells to treat mice, and hopefully one day humans, with spinal cord injury. Heilshorn explained,

“In our CIRM-funded studies, we learned a lot about how neural stem cells interact with materials. This lead us to realize that there’s another critical bottleneck that occurs even before the stage of transplantation: being able to generate a large enough number of high-quality stem cells for transplantation. We are developing materials to improve the transplantation of stem cell-derived therapies to patients with spinal cord injuries. Unfortunately, during the transplantation process, a lot of cells can get damaged. We are now creating injectable materials that prevent this cell damage during transplantation and improve the survival and engraftment of NSCs.”

An injectable material that promotes the expansion of large populations of clinical grade stem cells that can also differentiate into mature cells is highly desired by scientists pursuing the development of cell replacement therapies. Heilshorn and her team at Stanford have made significant progress on this front and are hoping that in time, this technology will prove effective enough to reach the clinic.

CIRM stories that caught our eye: UCSD team stops neuromuscular disease in mice, ALS trial enrolls 1st patients and Q&A with CIRM Prez

Ordinarily, we end each week at the Stem Cellar with a few stem cell stories that caught our eye. But, for the past couple of weeks we’ve been busy churning out stories related to our Month of CIRM blog series, which we hope you’ve found enlightening. To round out the series, we present this “caught our eye” blog of CIRM-specific stories from the last half of October.

Stopping neurodegenerative disorder with blood stem cells. (Karen Ring)

CIRM-funded scientists at the UC San Diego School of Medicine may have found a way to treat a progressive neuromuscular disorder called Fredreich’s ataxia (FA). Their research was published last week in the journal Science Translational Medicine.

FA is a genetic disease that attacks the nervous tissue in the spinal cord leading to the loss of sensory nerve cells that control muscle movement. Early on, patients with FA experience muscle weakness and loss of coordination. As the disease progresses, FA can cause scoliosis (curved spine), heart disease and diabetes. 1 in 50,000 Americans are afflicted with FA, and there is currently no effective treatment or cure for this disease.

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In this reconstituted schematic, blood stem cells transplanted in a mouse model of Friedreich’s ataxia differentiate into microglial cells (red) and transfer mitochondrial protein (green) to neurons (blue), preventing neurodegeneration. Image courtesy of Stephanie Cherqui, UC San Diego School of Medicine.

UCSD scientists, led by CIRM grantee Dr. Stephanie Cherqui, found in a previous study that transplanting blood stem and progenitor cells was an effective treatment for preventing another genetic disease called cystinosis in mice. Cherqui’s cystinosis research is currently being funded by a CIRM late stage preclinical grant.

In this new study, the UCSD team was curious to find out whether a similar stem cell approach could also be an effective treatment for FA. The researchers used an FA transgenic mouse model that was engineered to harbor two different human mutations in a gene called FXN, which produces a mitochondrial protein called frataxin. Mutations in FXN result in reduced expression of frataxin, which eventually leads to the symptoms experienced by FA patients.

When they transplanted healthy blood stem and progenitor cells (HSPCs) from normal mice into FA mice, the cells developed into immune cells called microglia and macrophages. They found the microglia in the brain and spinal cord and the macrophages in the spinal cord, heart and muscle tissue of FA mice that received the transplant. These normal immune cells produced healthy frataxin protein, which was transferred to disease-affected nerve and muscle cells in FA mice.

Cherqui explained their study’s findings in a UC San Diego Health news release:

“Transplantation of wildtype mouse HSPCs essentially rescued FA-impacted cells. Frataxin expression was restored. Mitochondrial function in the brains of the transgenic mice normalized, as did in the heart. There was also decreased skeletal muscle atrophy.”

In the news release, Cherqui’s team acknowledged that the FA mouse model they used does not perfectly mimic disease progression in humans. In future studies, the team will test their method on other mouse models of FA to ultimately determine whether blood stem cell transplants will be an effective treatment option for FA patients.

Brainstorm’s CIRM funded clinical trial for ALS enrolls its first patients
“We have been conducting ALS clinical trials for more than two decades at California Pacific Medical Center (CPMC) and this is, by far, the most exciting trial in which we have been involved to date.”

Those encouraging words were spoken by Dr. Robert Miller, director of CPMC’s Forbes Norris ALS Research Center in an October 16th news release posted by Brainstorm Cell Therapeutics. The company announced in the release that they had enrolled the first patients in their CIRM-funded, stem cell-based clinical trial for the treatment of amyotrophic lateral sclerosis (ALS).

BrainStorm

Also known as Lou Gehrig’s disease, ALS is a cruel, devastating disease that gradually destroys motor neurons, the cells in the brain or spinal cord that instruct muscles to move. People with the disease lose the ability to move their muscles and, over time, the muscles atrophy leading to paralysis. Most people with ALS die within 3 to 5 years from the onset of symptoms and there is no effective therapy for the disease.

Brainstorm’s therapy product, called NurOwn®, is made from mesenchymal stem cells that are taken from the patient’s own bone marrow. These stem cells are then modified to boost their production and release of factors, which are known to help support and protect the motor neurons destroyed by the disease. Because the cells are derived directly from the patient, no immunosuppressive drugs are necessary, which avoids potentially dangerous side effects. The trial aims to enroll 200 patients and is a follow up of a very promising phase 2 trial. CIRM’s $16 million grant to the Israeli company which also has headquarters in the United States will support clinical studies at multiple centers in California. And Abla Creasey, CIRM’s Senior Director of Strategic Infrastructure points out in the press release, the Agency support of this trial goes beyond this single grant:

“Brainstorm will conduct this trial at multiple sites in California, including our Alpha Clinics Network and will also manufacture its product in California using CIRM-funded infrastructure.”

An initial analysis of the effectiveness of NurOwn® in this phase 3 trial is expected in 2019.

CIRM President Maria Millan reflects on her career, CIRM’s successes and the outlook for stem cell biology 

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Maria T. Millan, M.D., CIRM President and CEO

RegMedNet a networking website that provides content related to the regenerative medicine community, published an interview this morning with Maria Millan, M.D., CIRM’s new President and CEO. The interview covers the impressive accomplishments that Dr. Millan had achieved before coming to CIRM, with details that even some of us CIRM team members may not have been aware of. In addition to describing her pre-CIRM career, Dr. Millan also describes the Agency’s successes during her term as Vice President of CIRM’s Therapeutics group and she gives her take on future of Agency and the stem cell biology field in general over the next five years and beyond. File this article under “must read”.

Turning the corner with the FDA and NIH; CIRM creates new collaborations to advance stem cell research

FDAThis blog is part of the Month of CIRM series on the Stem Cellar

A lot can change in a couple of years. Just take our relationship with the US Food and Drug Administration (FDA).

When we were putting together our Strategic Plan in 2015 we did a survey of key players and stakeholders at CIRM – Board members, researchers, patient advocates etc. – and a whopping 70 percent of them listed the FDA as the biggest impediment for the development of stem cell treatments.

As one stakeholder told us at the time:

“Is perfect becoming the enemy of better? One recent treatment touted by the FDA as a regulatory success had such a high clinical development hurdle placed on it that by the time it was finally approved the standard of care had evolved. When it was finally approved, five years later, its market potential had significantly eroded and the product failed commercially.”

Changing the conversation

To overcome these hurdles we set a goal of changing the regulatory landscape, finding a way to make the system faster and more efficient, but without reducing the emphasis on the safety of patients. One of the ways we did this was by launching our “Stem Cell Champions” campaign to engage patients, patient advocates, the public and everyone else who supports stem cell research to press for change at the FDA. We also worked with other organizations to help get the 21st Century Cures Act passed.

21 century cures

Today the regulatory landscape looks quite different than it did just a few years ago. Thanks to the 21st Century Cures Act the FDA has created expedited pathways for stem cell therapies that show promise. One of those is called the Regenerative Medicine Advanced Therapy (RMAT) designation, which gives projects that show they are both safe and effective in early-stage clinical trials the possibility of an accelerated review by the FDA. Of the first projects given RMAT designation, three were CIRM-funded projects (Humacyte, jCyte and Asterias)

Partnering with the NIH

Our work has also paved the way for a closer relationship with the National Institutes of Health (NIH), which is looking at CIRM as a model for advancing the field of regenerative medicine.

In recent years we have created a number of innovations including introducing CIRM 2.0, which dramatically improved our ability to fund the most promising research, making it faster, easier and more predictable for researchers to apply. We also created the Stem Cell Center  to make it easier to move the most promising research out of the lab and into clinical trials, and to give researchers the support they need to help make those trials successful. To address the need for high-quality stem cell clinical trials we created the CIRM Alpha Stem Cell Clinic Network. This is a network of leading medical centers around the state that specialize in delivering stem cell therapies, sharing best practices and creating new ways of making it as easy as possible for patients to get the care they need.

The NIH looked at these innovations and liked them. So much so they invited CIRM to come to Washington DC and talk about them. It was a great opportunity so, of course, we said yes. We expected them to carve out a few hours for us to chat. Instead they blocked out a day and a half and brought in the heads of their different divisions to hear what we had to say.

A model for the future

We hope the meeting is, to paraphrase Humphrey Bogart at the end of Casablanca, “the start of a beautiful friendship.” We are already seeing signs that it’s not just a passing whim. In July the NIH held a workshop that focused on what will it take to make genome editing technologies, like CRISPR, a clinical reality. Francis Collins, NIH Director, invited CIRM to be part of the workshop that included thought leaders from academia, industry and patients advocates. The workshop ended with a recommendation that the NIH should consider building a center of excellence in gene editing and transplantation, based on the CIRM model (my emphasis).  This would bring together a multidisciplinary disease team including, process development, cGMP manufacturing, regulatory and clinical development for Investigational New Drug (IND) filing and conducting clinical trials, all under one roof.

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Dr. Francis Collins, Director of the NIH

In preparation, the NIH visited the CIRM-funded Stem Cell Center at the City of Hope to explore ways to develop this collaboration. And the NIH has already begun implementing these suggestions starting with a treatment targeting sickle cell disease.

There are no guarantees in science. But we know that if you spend all your time banging your head against a door all you get is a headache. Today it feels like the FDA has opened the door and that, together with the NIH, they are more open to collaborating with organizations like CIRM. We have removed the headache, and created the possibility that by working together we truly can accelerate stem cell research and deliver the therapies that so many patients desperately need.