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.

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Inspiring the next generation of stem cell scientists

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SPARK students at the 2017 Annual Meeting at the City of Hope.

“The technological breakthroughs that will be happening over the next few years – it’s your generation of scientists that will make this happen.”

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John Zaia

Dr. John Zaia, the Director of City of Hope’s Center for Gene Therapy, directed these words to a group of 55 talented high school students attending the 2017 CIRM SPARK meeting.

SPARK stands for Summer Program to Accelerate Regenerative Medicine Knowledge. Students in the program spend their summer tackling difficult stem cell research projects in the lab, attending scientific workshops and lectures, and participated in patient engagement activities.

At the end of the summer, SPARK students from seven different programs at institutions and universities across California attend the annual SPARK meeting. At this gathering, students present their research to researchers and their families. They also hear about the progress in developing stem cell therapies from scientists and doctors and about exciting career paths in science and STEM fields from SPARK alumni.

The program is an excellent way for high school students to get their “research feet” wet. They are trained in basic lab and stem cell techniques and are assigned to a mentor who guides them through their research project.

Many of the students who participate in our SPARK programs go on to prestigious colleges to pursue degrees in science, medicine, and engineering. You can read some of these stories on our blog here and here.

At CIRM, we are invested in educating the next generation of stem cell scientists. Our Vice-Chair of the CIRM Board, Sen. Art Torres, said it perfectly at this year’s SPARK meeting:

“I just want to thank you for being part of this program. We are very proud of each and every one of you and we expect great things in the future.”

Check out this short video, produced by City of Hope, which features highlights from our 2017 SPARK meeting at the City of Hope. As you will see, this program is not only fun, but is a one-in-a-lifetime experience.

If you’re interested in learning more about our SPARK program or applying to be a SPARK intern, visit our website for more information. SPARK programs typically accept applications in December or early in the year. Each program has its own eligibility requirements and application process and you can find out that information on the individual SPARK program websites listed on our CIRM SPARK webpage.

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’s Clinical Dashboard: An Interactive Guide Makes Learning About Stem Cell Trials Easier

This blog is part of the Month of CIRM series on the Stem Cellar.

The questions we get most frequently from members of the public are about our clinical trials. Typically, people want to know what stem cell-based trials our Agency is funding or whether we’re funding trials for specific diseases or disorders that either they or their loved one are afflicted with.

During these conversations, we refer people to our website’s clinical trials page, which lists all of the trials CIRM has funded since our Agency was established in 2004. This page previously featured a simple table (see image below) that listed basic information about CIRM-funded trials including links to CIRM grants and to trial details on clinicaltrials.gov. This table was not the most exciting way to feature our clinical portfolio, but it did what it needed to do at the time.

CIRM’s former clinical trials table.

Here’s where I reference Bob Dylan’s famous lyric, “the times, they are a-changing”. CIRM’s clinical portfolio has rapidly expanded from 17 funded trials to 40 since the launch of our Strategic Plan in 2016. That’s 23 new trials in less than two years. The number of CIRM-funded trials will continue to climb steadily each year as we strive to reach our Strategic Plan’s goal of funding an additional 27 new trials by 2020.

This rapid expansion in our clinical portfolio is very exciting because it brings us closer to achieving our mission of accelerating stem cell treatments to patients with unmet medical needs. It also means that it’s finally time to retire our old clinical trials table and replace it with something that does our expanding portfolio justice, and makes it easier for anyone who is interested to learn about the trials we’re funding.

That something is already here and it’s called the Clinical Dashboard. It’s an interactive Dashboard that allows users to filter through CIRM’s clinical portfolio by clicking on tabs for major disease indications. Users can also sort trials by disease area, investigator, organization, and the phase or status of the trial.

The CIRM Clinical Dashboard was launched in September, 2017.

The Dashboard is a snapshot of the essential information a scientist, patient, or member of the public needs to know about our trials. Users who want to learn more about a given trial, beyond what’s listed in the Dashboard, can click on the arrow in the “Detail” column. This takes users to a detailed trials page featuring information about the treatment being tested, the CIRM clinical award that funded the trial, information about trial’s design, goals and patient enrollment status, and any recently published news about the trial.

The details page also has resources specifically for patients including a link for patients to contact the trial sponsor to ask about trial eligibility and enrollment and links to general information about stem cell trials on the CIRM website and from other organizations.

You can learn more about specific CIRM-funded trials by clicking the “Detail” icon on the Dashboard.

With our new Clinical Dashboard, we hope to raise the visibility of CIRM’s expanding clinical trial portfolio and to provide an all-in-one resource that is useful for multiple audiences.

Dr. Maria Millan, President and CEO of CIRM, concluded:

“CIRM is a global leader in funding high-quality stem cell trials for patients. We created the Clinical Dashboard for our website so that people can easily access important information about CIRM-funded trials and the promising treatments they are testing. As our Agency continues to fund new trials, we hope the Clinical Dashboard will prove to be an invaluable resource for patients, the public, and the stem cell research community.”

Stem Cell Tools: Helping Scientists Understand Complex Diseases

Yesterday, we discussed a useful stem cell tool called the CIRM iPSC Repository, which will contain over 3000 human induced pluripotent stem cell (iPSC) lines – from patients and healthy individuals – that contain a wealth of information about human diseases. Now that scientists have access to these lines, they need the proper tools to study them. This is where CIRM’s Genomics Initiative comes into play.

Crunching stem cell data

In 2014, CIRM funded the Genomics Initiative, which created the Center of Excellence in Stem Cell Genomics (CESCG). The goal of the CESCG is to develop novel genomics and bioinformatics tools specifically for stem cell research. These technologies aim to advance our fundamental understanding of human development and disease mechanisms, improve current cell and tissue production methods, and accelerate personalized stem cell-based therapies.

The CESCG is a consortium between Stanford University, the Salk Institute and UC Santa Cruz. Together, the groups oversee or support more than 20 different research projects throughout California focused on generating and analyzing sequencing data from stem or progenitor cells. Sequencing technology today is not only used to decode DNA, but also used to study other genomic data like that provides information about how gene activity is regulated.

Many of the projects within the CESCG are using these sequencing techniques to define the basic genetic properties of specific cell types, and will use this information to create better iPSC-based tissue models. For example, scientists can determine what genes are turned on or off in cells by analyzing raw data from RNA sequencing experiments (RNA is like a photocopy of DNA sequences and is the cell’s way of carrying out the instructions contained in the DNA. This technology sequences and identifies all the RNA that is generated in a tissue or cell at a specific moment).  Single cell RNA sequencing, made possible by techniques such as Drop-seq mentioned in yesterday’s blog, are now further revealing the diversity of cell types within tissues and creating more exact reference RNA sequences to identify a specific cell type.  By comparing RNA sequencing data from single cells of stem cell-based models to previously referenced cell types, researchers can estimate how accurate, or physiologically relevant, those stem cell models are.

Such comparative analyses can only be done using powerful software that can compare millions of sequence data at the same time. Part of a field termed bioinformatics, these activities are a significant portion of the CESCG and several software tools are being created within the Initiative.  Josh Stuart, a faculty member at UC Santa Cruz School of Engineering and a primary investigator in the CESCG, explained their team’s vision:

Josh Stuart

“A major challenge in the field is recognizing cell types or different states of the same cell type from raw data. Another challenge is integrating multiple data sets from different labs and figuring out how to combine measurements from different technologies. At the CESCG, we’re developing bioinformatics models that trace through all this data. Our goal is to create a database of these traces where each dot is a cell and the curves through these dots explain how the cells are related to one another.”

Stuart’s hope is that scientists will input their stem cell data into the CESCG database and receive a scorecard that explains how accurate their cell model is based on a specific genetic profile. The scorecard will help will not only provide details on the identity of their cells, but will also show how they relate to other cell types found in their database.

The Brain of Cells

An image of a 3D brain organoid grown from stem cells in the Kriegstein Lab at UCSF. (Photo by Elizabeth DiLullo)

A good example of how this database will work is a project called the Brain of Cells (BOC). It’s a collection of single cell RNA sequencing data from thousands of fetal-derived brain cells provided by multiple labs. The idea is that researchers will input RNA sequencing data from the stem cell-derived brain cells they make in their labs and the BOC will give them back a scorecard that describes what types of cells they are and their developmental state by comparing them to the referenced brain cells.

One of the labs that is actively involved in this project and is providing the bulk of the BOC datasets is Arnold Kriegstein’s lab at UC San Francisco. Aparna Bhaduri, a postdoctoral fellow in the Kriegstein lab working on the BOC project, outlined the goal of the BOC and how it will benefit researchers:

“The goal of the Brain of Cells project is to find ways to leverage existing datasets to better understand the cells in the developing human brain. This tool will allow researchers to compare cell-based models (such as stem cell-derived 3D organoids) to the actual developing brain, and will create a query-able resource for researchers in the stem cell community.”

Pablo Cordero, a former postdoc in Josh Stuart’s lab who designed a bioinformatics tool used in BOC called SCIMITAR, explained how the BOC project is a useful exercise in combining single cell data from different external researchers into one map that can predict cell type or cell fate.

“There is no ‘industry standard’ at the moment,” said Cordero. “We have to find various ways to perform these analyses. Approximating the entire human cell lineage is the holy grail of regenerative medicine since in theory, we would have maps of gene circuits that guide cell fate decisions.”

Once the reference data from BOC is ready, the group will use a bioinformatics program called Sample Psychic to create the scorecards for outside researchers. Clay Fischer, project manager of the CESCG at UC Santa Cruz, described how Sample Psychic works:

Clay Fischer

“Sample Psychic can look at how often genes are being turned off and on in cells. It uses this information to produce a scorecard, which shows how closely the data from your cells maps up to the curated cell types and can be used to infer the probability of the cell type.”

The BOC group believes that the analyses and data produced in this effort will be of great value to the research community and scientists interested in studying developmental neuroscience or neurodegeneration.

What’s next?

The Brain of Cells project is still in its early stages, but soon scientists will be able to use this nifty tool to help them build better and more accurate models of human brain development and brain-related diseases.

CESCG is also pursuing stem cell data driven projects focused on developing similar databases and scorecards for heart cells and pancreatic cells. These genomics and bioinformatics tools are pushing the envelope to a day when scientists can connect the dots between how different cell states and cell fates are determined by computational analysis and leverage this information to generate better iPSC-based systems for disease modeling in the lab or therapeutics in the clinic.


Related Links:

Stem Cell Tools: Helping Scientists Model Complex Diseases

This blog is part of the Month of CIRM series and the first of two blogs focused on how CIRM-funded infrastructure initiatives are developing useful tools to advance stem cell research. 

Human stem cells are powerful tools for studying human disease.  Animal models like mice have been and continue to be important for studying physiological systems, but they are still different than human systems.  Other types of human cells studied in the lab often are isolated from cancers or modified to multiply indefinitely.  However, the genetic DNA blueprint of these modified cells are irreparably altered from the normal tissues that they came from.

Human pluripotent stem cells are unique in that they can be grown in the lab and turned into any type of normal cell in the body.  Many scientists now believe that creating such stem cell lines from patients and developing ‘disease-in-a-dish’ models will provide important insights that will lead to treatments for the disorders from which they came.  Challenges still remain to develop these models to their fullest potential.  Because the genetics underlying human disease is complex, detailed genetic information about each stem cell line, as well as a large number of lines  to represent the genetic variability between patients will be needed to make progress.

To address this need, CIRM funded the creation of the world’s largest induced pluripotent stem cell bank, which we call the CIRM iPSC Repository.  iPSCs are similar to embryonic stem cells in that they can develop into any cell type found in the body, but they differ in how they are derived. Scientists can take human skin or blood cells and genetically reprogram them into iPSCs that have the same genetic makeup, including any disease-causing mutations, as the person from which the original cells were taken. Embryonic stem cells, on the other hand, are derived from left over embryos donated by couples undergoing in vitro fertilization (IVF) treatments.

The CIRM iPSC Repository was established to harness the power of iPSCs as tools for disease modeling and drug discovery. The Repository currently offers scientists around the world access to over 1500 high-quality iPSC lines covering diseases of the brain, heart, liver, lung, and eye, and the collection will eventually hold over 3000 lines.  All iPSC lines are linked to publicly-accessible demographic and clinical information.

Making the Cell Lines

Making the iPSC Repository was no easy task – it took a village of doctors, scientists, patients and healthy volunteers. First, clinicians across California collected blood and skin samples from over 2800 people including individuals with common diseases, rare diseases and healthy controls. CIRM then awarded a grant to Cellular Dynamics International to create iPSC lines from these donors, and a second grant to the Coriell Institute to store and distribute the lines to interested labs around the world. Creating such a large number of lines in a single concerted effort has been a challenging logistical feat that has taken almost five years and is projected to finish in early 2018.

Joachim Hallmayer

We spoke with one of the tissue collectors, a scientist named Dr. Joachim Hallmayer at Stanford University, about the effort it took to obtain tissue samples for the Repository. Hallmayer is a Professor of Psychiatry and Behavioral Sciences at Stanford who studies Autism Spectrum Disorder (ASD) in children. With funding from a CIRM Tissue Collection for Disease Modeling award, Hallmayer collected tissue samples from children with ASD and children with normal development. His efforts resulted in the 164 ASD and 134 control samples for the Repository.

Hallmayer emphasized that each sample donation required significant attention and education from the clinical staff to the donor.  Communicating with patients and walking them through the consent process for donating their tissue for this purpose is an extremely important issue that is often overlooked. “Conveying information about the tissue collection process to patients takes a lot of time. However, deconstructing the consent process is essential for patients to understand what they are donating and why,” explained Hallmayer.

Now that the ASD lines are available, Hallmayer and his colleague Dr. Ruth O’Hara are formulating a plan to model ASD in a dish by differentiating the iPSC lines into neurons affected by this disorder. Says O’Hara:

Ruth O’Hara

“While the examination of live tissue from other organ systems has become increasingly viable, examining live neurons from patients with brain disorders has simply not been possible. Using iPSC-derived neurons, for the first time we can study live nerve cells from actual patients and compare these cells to those from humans without the disorder.”

Using iPSCs to Model Psychiatric Disorders

Ultimately, the goal of iPSCs for modeling disease is to identify mechanisms and therapeutic targets for the disorders that they represent.  Studying a disease through a single iPSC line may not shed enough light on that disorder.  Just as people have diverse traits, the way that a disease can affect individuals is also diverse.  Studying large numbers of lines in a time and cost-efficient manner that represent these diverse traits, and the genetic causes that underlie them, can be a powerful method to understand and address diseases.

 To leverage the iPSC collection for this purpose, CIRM and a group of scientists at the Broad Institute’s Stanley Center for Psychiatric Research and Harvard University have entered into a collaboration to study psychiatric disorders such as ASD.  Because the donor samples were collected on the basis of clinical information, the genetic information about what caused their disease remains unknown.  Therefore, the Stanley Center will embark on whole genome sequencing (WGS) of hundreds of lines from the CIRM iPSC repository. Adding donor WGS sequence information to the CIRM repository will significantly increase its value, as scientists will be able to use DNA sequence information to select the ideal lines for disease modeling and therapeutic discovery efforts. The collaboration aims to identify the genes that shape neuronal phenotypes in iPSC-derived neurons from patients with psychiatric disorders.

“A central challenge today is to discover how inherited genetic variation gives rise to functional variation in the properties of neurons and other cells,” said Steven McCarroll, Director of Genetics at the Broad Institute’s Stanley Center for Psychiatric Research, and associate professor at Harvard Medical School’s Department of Genetics. “We hope with the analysis of cells from very large numbers of genetically diverse individuals will begin to address longstanding problems at the interface of human genetics and biology.”

iPSC derived neurons growing in a dish. (Image courtesy of Ralda Nehme, Research Scientist at the Broad Institute).

Such efforts require technologies such as Drop-seq, developed in the McCarroll lab, where genome-wide expression of thousands of separate cells can be analyzed in one experiment. These efforts also rely on scaling functional analysis of stem cell-based disease models, a vexing bottleneck for the field. “The CIRM iPSC Repository is the largest and most ambitious of its kind”, said Kevin Eggan, Professor of Stem Cell and Regenerative Biology at Harvard University, and Director of Stem Cell Biology at the Broad Institute’s Stanley Center for Psychiatric Research. Efforts underway in Dr. Eggan’s lab are directed at developing approaches to analyze large numbers of stem cell lines in parallel.

“The scale of the CIRM iPSC collection will allow us to investigate how variation that is common among many of us predisposes certain individuals to major mental illnesses such as autism and other neurodevelopmental disorders. We are incredibly excited about entering this long-term collaboration.”

Members of the Eggan and McCarroll labs at the Broad Institute’s Stanley Center for Psychiatric Research. (Image courtesy of Kiki Lilliehook)

From Cell Lines to Data

It’s clear from these stories, that the iPSC Repository is a unique and powerful tool for the stem cell research community. But for the rewards to be truly reaped, more tools are needed that will help scientists study these cell lines. This is where the CIRM Genomics Initiative comes into play.

Be sure to read Part 2 of our Stem Cell Tools series tomorrow to find out how our Genomics Initiative is funding the development of genomic and bioinformatics tools that will allow scientists to decipher complex stem cell data all the way from mapping the developmental states of cells to predicting the accuracy of stem cell-based models.

This blog was written in collaboration with Dr. Kiki Lilliehook, the Manager of the Stem Cell Program at the Stanley Center for Psychiatric Research at the Broad Institute in Cambridge, Massachusetts.

Can Stem Cell Therapies Help ALS Patients?

A scientist’s fifteen-year journey to develop a stem cell-based therapy that could one day help ALS patients.

Jan Kaufman

Photo of Clive Svendsen (top left) and Jan & Jeff Kaufman

“Can stem cells help me Clive?”

The sentence appeared slowly on a computer screen, each character separated by a pause while its author searched for the next character using a device controlled by his eye muscle.

The person asking the question was Jeff Kaufman, a Wisconsin man in his 40s completely paralyzed by amyotrophic lateral sclerosis (ALS). On the receiving end was Clive Svendsen, PhD, then a scientist at the University of Wisconsin-Madison, determined to understand how stem cells could help patients like Jeff.

Also known as Lou Gehrig’s disease, ALS is a rapid, aggressive neurodegenerative disease with a two to four-year life expectancy. ALS destroys the nerve cells that send signals from the brain and spinal cord to the muscles that control movement. Denervation, or loss of nerves, causes muscle weakness and atrophy, leaving patients unable to control their own bodies. Currently there are two FDA-approved ALS drugs in the US – riluzole and a new drug called edaravone (Radicava). However, they only slow disease progression in some ALS patients by a few months and there are no effective treatments that stop or cure the disease.

Given this poor prognosis, making ALS the focus of his research career was an easy decision. However, developing a therapeutic strategy was challenging to Svendsen. “The problem with ALS is we don’t know the cause,” he said. “Around 10% of ALS cases are genetic, and we know some of the genes involved, but 90% of cases are sporadic.” He explained that this black box makes it difficult for scientists to know where to start when trying to develop treatments for sporadic ALS cases that have no drug targets.

From Parkinson’s disease to ALS

Svendsen, who moved to Cedars-Sinai in Los Angeles to head the Cedars-Sinai Board of Governors Regenerative Medicine Institute in 2010, has worked on ALS for the past 15 years. Before that, he studied Parkinson’s disease, a long-term neurodegenerative disorder that affects movement, balance and speech. Unlike ALS, Parkinson’s patients have a longer life expectancy and more treatment options that alleviate symptoms of the disease, making their quality of life far better than ALS patients.

Clive Svendsen, PhD, Director, Regenerative Medicine Institute. (Image courtesy of Cedars-Sinai)

“I chose to work on ALS mainly because of the effects it has on ALS families,” explained Svendsen. “Being normal one day, and then becoming rapidly paralyzed was hard to see.”

The transition from Parkinson’s to ALS was not without a scientific reason however. Svendsen was studying how an important growth factor in the brain called Glial Cell Line-Derived Neurotrophic Factor or GDNF could be used to protect dopamine neurons in order to treat Parkinson’s patients. However other research suggested that GDNF was even more effective at protecting motor neurons, the nerve cells destroyed by ALS.

Armed with the knowledge of GDNF’s ability to protect motor neurons, Svendsen and his team developed an experimental stem cell-based therapy that they hoped would treat patients with the sporadic form of ALS. Instead of using stem cells to replace the motor neurons lost to ALS, Svendsen placed his bets on making another cell type in the brain, the astrocyte.

Rooting for the underdog

Astrocytes are the underdog cells of the brain, often overshadowed by neurons that send and receive information from the central nervous system to our bodies. Astrocytes have many important roles, one of the most critical being to support the functions of neurons. In ALS, astrocytes are also affected but in a different way than motor neurons. Instead of dying, ALS astrocytes become dysfunctional and thereby create a toxic environment inhospitable to the motors neurons they are supposed to assist.

Fluorescent microscopy of astrocytes (red) and cell nuclei (blue). Image: Wikipedia.

“While the motor neurons clearly die in ALS, the astrocytes surrounding the motor neurons are also sick,” said Svendsen. “It’s a huge challenge to replace a motor neuron and make it grow a cable all the way to the muscle in an adult human. We couldn’t even get this to work in mice. So, I knew a more realistic strategy would be to replace the sick astrocytes in an ALS patients with fresh, healthy astrocytes. This potentially would have a regenerative effect on the environment around the existing motor neurons.”

The big idea was to combine both GDNF and astrocyte replacement. Svendsen set out to make healthy astrocytes from human brain stem cells that also produce therapeutic doses of GDNF and transplant these cells into the ALS patient spinal cord. Simply giving patients GDNF via pill wouldn’t work because the growth factor is unable to enter the brain or spinal cord tissue where it is needed. The hope, instead, was that the astrocytes would secrete the protective factor that would keep the patients’ motor neurons healthy and alive.

With critical funding from a CIRM Disease Team grant, Svendsen and his colleagues at Cedars-Sinai tested the feasibility of transplanting human brain stem cells (also referred to as neural progenitor cells) that secreted GDNF into a rat model of ALS. Their results were encouraging – the neural progenitor cells successfully developed into astrocytes and secreted GDNF, which collectively protected the rat motor neurons.

Svendsen describes the strategy as “a double whammy”: adding both healthy astrocytes and GDNF secretion to protect the motor neurons. “Replacing astrocytes has the potential to rejuvenate the niche where the motor neurons are. I think that’s a very powerful experimental approach to ALS.”

A fifteen year journey from bench to bedside

With promising preclinical data under his belt, Svendsen and his colleagues, including Robert Baloh, MD, PhD, director of neuromuscular medicine at the Cedars-Sinai Department of Neurology, and neurosurgeon J. Patrick Johnson, MD, designed a clinical trial that would test this experimental therapy in ALS patients. In October 2016, CIRM approved funding for a Phase I/IIa clinical trial assessing the safety of this novel human neural progenitor cell and gene therapy.

Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, and Robert Baloh, MD, PhD, director of neuromuscular medicine in the Cedars-Sinai Department of Neurology, in the lab. Svendsen is the sponsor of a current ALS clinical trial at Cedars-Sinai and the overall director of the program. Baloh is the principal investigator for the clinical trial. (Image courtesy of Cedars-Sinai)

This is a first-in-human study, and as such, the U.S. Food and Drug Administration (FDA) required the team to transplant the cells into only one side of the lumbar spinal cord, which effectively means that only one of the patient’s legs will get the treatment. This will allow for a comparison of the function and progression of ALS in the leg on the treated side of the spinal cord compared with the leg on the untreated side.

The trial was approved to treat a total of 18 patients and started in May 2017.

 Svendsen, who first started working on ALS back in 2002, describes his path to the clinic as a “very long and windy road.” He emphasized that this journey wouldn’t be possible without the hard work of his team, Cedars-Sinai and financial support from CIRM.

“It took ten years of preclinical studies and an enormous amount of work from many different people. Just producing the cells that we’re going to use took three years and a lot of trials and tribulations to make it a clinically viable product. It was really thanks to CIRM’s funding and the support of Cedars-Sinai that we got through it all. Without that kind of infrastructure, I can safely say we wouldn’t be here today.”

This “behind-the-scenes” view of how much time and effort it takes to translate a stem cell therapy from basic research into the clinic isn’t something that the public is often exposed to or aware of. Just as “Rome wasn’t built in a day,” Svendsen stressed that good quality stem cell trials take time, and that it’s important for people know how complicated these trials are.

It’s all about the patients

So, what motivates Svendsen to continue this long and harrowing journey to develop a treatment for ALS? He said the answer is easy. “I’m doing it for the patients,” he explained. “I’m not doing this for the money or glory. I just want to develop something that works for ALS, so we can help these patients.”

Svendsen revisited his story about Jeff Kaufman, a man he befriended at the Wisconsin ALS Chapter in 2003. Jeff had three daughters and a son, a wonderful wife, and was a successful lawyer when he was diagnosed with ALS.

“Jeff had basically everything, and then he was stricken with ALS. I still remember going to his house and he could only move his eyes at that point. He tapped out the words ‘Can stem cells help me Clive?’ on his computer screen. And my heart sank because I knew how much and how long it was going to take. I was very realistic so I said, ‘Yes Jeff, but it’s going to take time and money. And even then, it’s a long shot.’ And he told me to go for it, and that stuck in my brain.”

It’s people like Jeff that make Svendsen get out of bed every morning and doggedly pursue a treatment for ALS. Sadly, Jeff passed away due to complications from ALS in 2010. Svendsen says what Jeff and other patients go through is tragic and unfair.

“There’s a gene that goes along with ALS and it’s called the ‘nice person gene,’” he said. “People with ALS are nice. I can’t explain it, but neurologists would say the same thing. You feel like it’s just not fair that it happens to those people.”

The future of stem cell therapies for ALS

It’s clear from speaking with Svendsen, that he is optimistic about the future of stem cell-based therapies for ALS. Scientists still need to unravel the actual causes of ALS. But the experimental stem cell treatments currently in development, including Svendsen’s, will hopefully prove effective at delaying disease progression and give ALS patients more quality years to live.

In the meantime, what concerns Svendsen is how vulnerable ALS patients are to being misled by unapproved stem cell clinics that claim to have cures. “Unfortunately, there are a lot of charlatans out there, and there are a lot of false claims being made. People feed off the desperation that you have in ALS. It’s not fair, and it’s completely wrong. They’ll mislead patients by saying ‘For $40,000 you can get a cure!’”

Compelling stories of patients cured of knee pain or diseases like ALS with injections of their own adult stem cells pop up in the news daily. Many of these stories refer to unapproved treatments from clinics that don’t provide scientific evidence that these treatments are safe and effective. Svendsen said there are reasonable, research-backed trials that are attempting to use adult stem cells to treat ALS. He commented, “I think it’s hard for the public to wade through all of these options and understand what’s real and what’s not real.”

Svendsen’s advice for ALS patients interested in enrolling in a stem cell trial or trying a new stem cell treatment is to be cautious. If a therapy sounds too good to be true, it probably is, and if it costs a lot of money, it probably isn’t legitimate, he explained.

He also wants patients to understand the reality of the current state of ALS stem cell trials. The approved stem cell trials he is aware of are not at the treatment stage yet.

“If you’re enrolled in a stem cell trial that is funded and reputable, then they will tell you honestly that it’s not a treatment. There is currently no approved treatment using stem cells for ALS,” Svendsen said.

This might seem like discouraging news to patients who don’t have time to wait for these trials to develop into treatments, but Svendsen pointed out that the when he started his research 15 years ago, the field of stem cell research was still in its infancy. A lot has been accomplished in the past decade-and-a-half and with talented scientists dedicated to ALS research like Svendsen, the next 15 years will likely offer new insights into ALS and hopefully stem cell-based treatments for a devastating disease that has no cure.

Svendsen hopes that one day, when someone like Jeff Kaufman asks him “Can stem cells help me Clive?” He’ll be able to say, yes they can, yes they can.

CIRM-Funded Clinical Trials Targeting the Heart, Pancreas, and Kidneys

This blog is part of our Month of CIRM series, which features our Agency’s progress towards achieving our mission to accelerate stem cell treatments to patients with unmet medical needs.

This week, we’re highlighting CIRM-funded clinical trials to address the growing interest in our rapidly expanding clinical portfolio. Today we are featuring trials in our organ systems portfolio, specifically focusing on diseases of the heart/vasculature system, the pancreas and the kidneys.

CIRM has funded a total of nine trials targeting these disease areas, and eight of these trials are currently active. Check out the infographic below for a list of our currently active trials.

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-Funded Clinical Trials Targeting Brain and Eye Disorders

This blog is part of our Month of CIRM series, which features our Agency’s progress towards achieving our mission to accelerate stem cell treatments to patients with unmet medical needs.

 This week, we’re highlighting CIRM-funded clinical trials to address the growing interest in our rapidly expanding clinical portfolio. Our Agency has funded a total of 40 trials since its inception. 23 of these trials were funded after the launch of our Strategic Plan in 2016, bringing us close to the half way point of our goal to fund 50 new clinical trials by 2020.

Today we are featuring CIRM-funded trials in our neurological and eye disorders portfolio.  CIRM has funded a total of nine trials targeting these disease areas, and seven of these trials are currently active. Check out the infographic below for a list of our currently active trials.

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.


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