Month of CIRM

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

/ Karen Ring / Leave a comment

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.”

Getting faster, working smarter: how changing the way we work is paying big dividends

/ Kevin McCormack / Leave a comment

This blog is part of the Month of CIRM series

Speeding up the way you do things isn’t always a good idea. Just ask someone who got a ticket for going 65mph in a 30mph zone. But at CIRM we have found that doing things at an accelerated pace is paying off in a big way.

When CIRM started back in 2004 we were, in many ways, a unique organization. That meant we pretty much had to build everything from scratch, creating our own ways of asking for applications, reviewing those applications, funding them etc. Fast forward ten years and it was clear that, as good a job as we did in those early days, there was room for improvement in the way we operated.

So we made some changes. Big changes.

We adopted as our mantra the phrase “operational excellence.” It doesn’t exactly trip off the tongue but it does reflect what we were aiming for. The Business Dictionary defines operational excellence as:

 “A philosophy of the workplace where problem-solving, teamwork, and leadership results in the ongoing improvement in an organization.”

We didn’t want to just tinker with the way we worked, we wanted to reinvent every aspect of our operation. To do that we involved everyone in the operation. We held a series of meetings where everyone at CIRM, and I do mean everyone, was invited to join in and offer their ideas on how to improve our operation.

CIRM2.0_Logo

The end result was CIRM 2.0. At the time we described it as “a radical overhaul” of the way we worked. That might have been an understatement. We increased the speed, frequency and volume of the programs we offered, making it easier and more predictable for researchers to apply to us for funding, and faster for them to get that funding if they were approved.

For example, before 2.0 it took almost two years to go from applying for funding for a clinical trial to actually getting that funding. Today it takes around 120 days.

But it’s not just about speed. It’s also about working smarter. In the past if a researcher’s application for funding for a clinical trial failed it could be another 12 months before they got a chance to apply again. With many diseases 12 months could be a death sentence. So we changed the rules. Now if you have a project ready for a clinical trial you can apply any time. And instead of recommending or not recommending a project, basically voting it up or down, our independent panel of expert reviewers now give researchers with good but not great applications constructive feedback, enabling the researchers to make the changes needed to improve their project, and reapply for funding within 30 days.

This has not only increased the number of applications for clinical trials, it has also increased the quality of those applications.

We made similar changes in our Discovery and Translation programs. Increasing the frequency of each award, making it easier for researchers to know when the next round of funding was coming up. And we added incentives to encourage researchers to move successful projects on to the next level. We wanted to create a pipeline of the most promising projects steadily moving towards the clinic.

The motivation to do this comes from our patients. At CIRM we are in the time business. Many of the patients who are looking to stem cells to help them don’t have the luxury of time; they are rapidly running out of it. So we have a responsibility to do all we can to reduce the amount of time it takes to get the most promising therapies to them, without in any way compromising safety and jeopardizing their health.

By the end of 2016 those changes were very clearly paying dividends as we increased the frequency of reviews and the number of projects we reviewed but at the same time decreased the amount of time it took us to do all that.

Slide1

But we are not done yet. We have done a good job of improving the way we work. But there is always room to be even better, to go even faster and be more efficient.

We are not done accelerating. Not by a long shot.

Stem Cell Tools: Helping Scientists Understand Complex Diseases

/ Karen Ring / Leave a comment

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

/ Karen Ring / 1 Comment

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.

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

/ Geoffrey Lomax Dr. PH / Leave a comment

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

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

The answer is the CIRM Alpha Stem Cell Clinics Network.

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

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

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

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

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

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

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

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

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

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

How Can I Learn More?

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

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

CIRM-Funded Clinical Trials Targeting Brain and Eye Disorders

/ Karen Ring / 1 Comment

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.

A month of CIRM: Gauging our progress to plan for our future

/ Kevin McCormack / 1 Comment

Every once in a while, it’s a good idea to take a step back and look at what you’ve done, what you’ve achieved. It’s not about identifying the things that have gone well and patting yourself on the back for them; it’s more a matter of assessing where you started, what your goals were, where you succeeded, where you fell short, and where you want to go in the future.

So during the month of October, we are going to be taking a look back at what CIRM has done in the years since we were created by the people of California in 2004. We want to take stock of what we have done and how that has helped shape the agency we are today, and the agency we hope to be in the future.

Each week we will highlight a different area, starting with a look at the projects we are funding in clinical trials – how after our first ten years we had seventeen projects in clinical trials, and today that number is 35 and counting. We’ll also provide updates on our infrastructure programs like the Alpha Stem Cell Clinics Network and the Stem Cell Center – programs that play a critical role in accelerating the development and delivery of high quality stem cell treatments to patients with unmet medical needs.

Over the course of the next few weeks, we’ll show how the way we work has changed and evolved as the field of stem cell research progressed, and how we have tried to be more responsive both to the needs of researchers and patients.

We’ll also be taking a look at the people who have helped play a key role in shaping us, from the scientists who do the work to the patient advocates who are relentless champions of stem cell research. We’ll even profile some of the unsung heroes here at CIRM.

But even as we look back we’re going to use that to frame our future, to see where we are going. We have some big goals for the next few years – as laid out in our Strategic Plan – and we are working hard to get there. By reflecting on the past, using the experienced gained and lessons learned, we hope to have a much clearer view of what we need to do in the years ahead.

Like any good driver we are focused on what is in front of us; but every once in a while, it’s not a bad idea to take a look in the rearview mirror and see what’s behind you, where you have come from.

During October we’re taking a quick look in our rear view mirror. (photo source)