A stepping stone for bringing stem cell therapy to patients with ALS

ALS Picture1

Imagine being told that you have a condition that gradually causes you to lose the ability to control your body movements, from picking up a pencil to walking to even breathing. Such is the reality for the nearly 6,000 people who are diagnosed with amyotrophic lateral sclerosis (ALS) every year, in the United States alone.

ALS, also known as Lou Gehrig’s disease, is a neurodegenerative disease that causes the degradation of motor neurons, or nerves that are responsible for all voluntary muscle movements, like the ones mentioned above. It is a truly devastating disease with a particularly poor prognosis of two to five years from the time of diagnosis to death. There are only two approved drugs for ALS and these do not stop it but only slow progression of the disease; and even then only for some patients, not all.

A ray of hope for such a bleak treatment landscape, has been the advent of stem cell therapy options over the past decade. Of particular excitement is the recent discovery made Nasser Aghdami’s group at the Royan Institute for Stem Cell Biology and Technology in Iran.

Two small Phase I clinical trials detailed in Cell Journal demonstrated that injecting mesenchymal stem cells (MSCs), derived from the patient’s own bone marrow, was safe when administered via injection into the bloodstream or the spinal cord. Previous studies had shown that MSCs both revived motor neurons and extended the lifespan in a rodent model of the disease.

In humans, many studies have shown that MSCs taken from bone marrow are safe for use in humans, but these studies have disagreed about whether injection via the bloodstream or spinal cord route is the most effective way to deliver the therapy. This report confirms that both routes of administration are safe as no adverse clinical events were observed for either group throughout the study time frame.

While an important stepping stone, there is still a long way to go. For example, while no adverse clinical events were observed in either group, the overall ALS-FRS score, a clinical scale to determine ALS disease progression, worsened in all patients over the course of the study. Whether this was just due to natural progression of the disease, or because of the stem cell treatment is difficult to determine given the small size of the cohort.

One reason the scientists suggest that could explain the disease decline is because the MSCs were taken from the ALS patients themselves, which means these cells were likely not functioning optimally prior to re-introduction into the patient. To remedy this, they hope to test the effect of MSCs taken from healthy donors in both injection routes in the future. They also need a larger cohort of patients to determine whether or not there is a difference in the therapeutic effect of administering stem cells via the two different routes.

While it may seem that the results from this clinical trial are not particularly groundbreaking or innovative, it is important to remember that these incremental improvements through clinical trials are critical for bringing safe and effective therapies to the market. For more information on the different phases of clinical trials, please refer to this video.

CIRM is also funding clinical trials targeting ALS. One is a Phase 1 trial out of Cedars-Sinai Medical Center and another is a Phase 3 trial with the company Brainstorm Cell Therapeutics.

Has Regenerative Medicine Come of Age?

Signals logo

For the past few years the Signals blog site –  which offers an insiders’ perspectives on the world of regenerative medicine and stem cell research – has hosted what it calls a “Blog Carnival”. This is an event where bloggers from across the stem cell field are invited to submit a piece based on a common theme. This year’s theme is “Has Regenerative Medicine Come of Age?” Here’s my take on that question:

Many cultures have different traditions to mark when a child comes of age. A bar mitzvah is a Jewish custom marking a boy reaching his 13th birthday when he is considered accountable for his own actions. Among Latinos in the US a quinceañera is the name given to the coming-of-age celebration on a girl’s 15th birthday.

Regenerative Medicine (RM) doesn’t have anything quite so simple or obvious, and yet the signs are strong that if RM hasn’t quite come of age, it’s not far off.

For example, look at our experience at the California Institute for Regenerative Medicine (CIRM). When we were created by the voters of California in 2004 the world of stem cell research was still at a relatively immature phase. In fact, CIRM was created just six years after scientists first discovered a way to derive stem cells from human embryos and develop those cells in the laboratory. No surprise then that in the first few years of our existence we devoted a lot of funding to building world class research facilities and investing in basic research, to gain a deeper understanding of stem cells, what they could do and how we could use them to develop therapies.

Fast forward 14 years and we now have funded 49 projects in clinical trials – everything from stroke and cancer to spinal cord injury and HIV/AIDS – and our early funding also helped another 11 projects get into clinical trials. Clearly the field has advanced dramatically.

In addition the FDA last year approved the first two CAR-T therapies – Kymriah and Yescarta – another indication that progress is being made at many levels.

But there is still a lot of work to do. Many of the trials we are funding at the Stem Cell Agency are either Phase 1 or 2 trials. We have only a few Phase 3 trials on our books, a pattern reflected in the wider RM field. For some projects the results are very encouraging – Dr. Gary Steinberg’s work at Stanford treating people recovering from a stroke is tremendously promising. For others, the results are disappointing. We have cancelled some projects because it was clear they were not going to meet their goals. That is to be expected. These clinical trials are experiments that are testing, often for the first time ever in people, a whole new way of treating disease. Failure comes with the territory.

As the number of projects moving out of the lab and into clinical trials increases so too are the other signs of progress in RM. We recently held a workshop bringing together researchers and regulators from all over the world to explore the biggest problems in manufacturing, including how you go from making a small batch of stem cells for a few patients in an early phase clinical trial to mass producing them for thousands, if not millions of patients. We are also working with the National Institutes of Health and other stakeholders in discussing the idea of reimbursement, figuring out who pays for these therapies so they are available to the patients who need them.

And as the field advances so too do the issues we have to deal with. The discovery of the gene-editing tool CRISPR has opened up all sorts of possible new ways of developing treatments for deadly diseases. But it has also opened up a Pandora’s box of ethical issues that the field as a whole is working hard to respond to.

These are clear signs of a maturing field. Five years ago, we dreamed of having these kinds of conversations. Now they are a regular feature of any RM conference.

The simple fact that we can pose a question asking if RM has come of age is a sign all by itself that we are on the way.

Like little kids sitting in the back of a car, anxious to get to their destination, we are asking “Are we there yet?” And as every parent in the front seat of their car responds, “Not yet. But soon.”

Why having a wrinkled brain is a good thing

Brain_01

We normally associate wrinkles with aging, such as wrinkled skin. But there’s one organ that is wrinkled right from the time we are born. It’s our brain. And new research shows those wrinkles are not a sign of age but are, in fact, a sign of just how large and complex our brains are.

The wrinkles, according to U.C. Santa Barbara (UCSB) postdoctoral scholar Eyal Karzbrun, are vital to our development because they create a greater surface area giving our neurons, or brain nerve cells, more space to create connections and deliver information.

In an article in UCSB’s Daily Nexus, Karzbrun says while our knowledge of the brain is increasing there are still many things we don’t understand:

“The brain is a complex organ whose organization is essential to its function. Yet it is ‘assembled by itself’. How this assembly takes place and what physics come into play is fundamental to our understanding of the brain.”

Eyal Karzbrun

Eyal Karzbrun: Photo courtesy UCSB

Karzbrun used stem cells to create 3D clusters of brain cells, to better understand how they organize themselves. He said brains are like computers in the way they rely on surface area to process information.

“In order to be computationally strong and quick, what your brain does is take a lot of surface area and put it in a small volume. The cerebral cortex, which occupies most of the volume in your brain, has a unique architecture in which neurons are layered on the outer surface of the brain, and the bulk of the brain is composed of axons, [or] biological wire which interconnect the neurons.”

Karzbrun says gaining a deeper understanding of how the brain is formed, and why it takes the shape it does, may help us develop new approaches to treating problems in the brain.

 

Join us tomorrow at noon for “Ask the Stem Cell Team about Sickle Cell Disease”, a FaceBook Live Event

As an early kick off to National Sickle Cell Awareness Month – which falls in September every year – CIRM is hosting a “Ask the Stem Cell Team” FaceBook Live event tomorrow, August 28th, from noon to 1pm (PDT).

CIRMFaceBookLiveIcon4BeliveTV_v2

The live broadcast will feature two scientists and a patient advocate who are working hard to bring an end to sickle cell disease, a devastating, inherited blood disorder that largely targets the African-American community and to a lesser degree the Hispanic community.

You can join us by logging onto Facebook and going to this broadcast link: https://bit.ly/2o4aCAd

Also, make sure to “like” our FaceBook page before the event to receive a notification when we’ve gone live for this and future events. If you miss tomorrow’s broadcast, not to worry. We’ll be posting it on our Facebook video page, our website, and YouTube channel shortly afterwards.

We want to answer your most pressing questions, so please email them directly to us beforehand at info@cirm.ca.gov.

For a sneak preview here’s a short video featuring our patient advocate speaker, Adrienne Shapiro. And see below for more details about Ms. Shapiro and our two other guests.

Adrienne Shapiro [Video: Todd Dubnicoff/CIRM]

  • Dr. Donald B. KohnUCLA MIMG BSCRC Faculty 180118

    Donald Kohn, MD

    Don Kohn, M.D. is a professor in the departments of Pediatrics and Microbiology, Immunology and Molecular Genetics in UCLA’s Broad Stem Cell Research Center. Dr. Kohn has a CIRM Clinical Stage Research grant in support of his team’s Phase 1 clinical trial which is genetically modifying a patient’s own blood stem cells to produce a correct version of hemoglobin, the protein that is mutated in these patients, which causes abnormal sickle-like shaped red blood cells. These misshapen cells lead to dangerous blood clots, debilitating pain and even death. The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

  • Walters_Mark_200x250

    Mark Walters, MD

    Mark Walters, M.D., is a pediatric hematologist/oncologist and is director of the Blood & Marrow Transplantation Program at UCSF Benioff Children’s Hospital Oakland. Dr. Walters has a CIRM-funded Therapeutic Translation Research grant which aims to improve Sickle Cell Disease (SCD) therapy by preparing for a clinical trial that might cure SCD after giving back sickle gene-corrected blood stem cells – using cutting-edge CRISPR gene editing technology – to a person with SCD. If successful, this would be a universal life-saving and cost-saving therapy.

  • e90e6-adrienneshapiro

    Adrienne Shapiro

    Adrienne Shapiro is a patient advocate for SCD and the co-founder of the Axis Advocacy SCD patient education and support website. Shapiro is the fourth generation of mothers in her family to have children born with sickle cell disease.  She is vocal stem cell activist, speaking to various groups about the importance of CIRM’s investments in both early stage research and clinical trials. In January, she was awarded a Stem Cell and Regenerative Medicine Action Award at the 2018 World Stem Cell Summit.

Stem cell stories that caught our eye: CIRM-funded scientist wins prestigious prize and a tooth trifecta

CIRM-grantee wins prestigious research award

Do we know how to pick ‘em or what? For a number of years now we have been funding the work of Stanford’s Dr. Marius Wernig, who is doing groundbreaking work in helping advance stem cell research. Just how groundbreaking was emphasized this week when he was named as the winner of the 2018 Ogawa-Yamanaka Stem Cell Prize.

WernigMarius_Stanford

Marius Wernig, MD, PhD. [Photo: Stanford University]

The prestigious award, from San Francisco’s Gladstone Institutes, honors Wernig for his innovative work in developing a faster, more direct method of turning ordinary cells into, for example, brain cells, and for his work advancing the development of disease models for diseases of the brain and skin disorders.

Dr. Deepak Srivastava, the President of Gladstone, announced the award in a news release:

“Dr. Wernig is a leader in his field with extraordinary accomplishments in stem cell reprogramming. His team was the first to develop neuronal cells reprogrammed directly from skin cells. He is now investigating therapeutic gene targeting and cell transplantation–based strategies for diseases with mutations in a single gene.”

Wernig was understandably delighted at the news:

“It is a great honor to receive this esteemed prize. My lab’s goal is to discover novel biology using reprogrammed cells that aids in the development of effective treatments.”

Wernig will be presented with the award, and a check for $150,000, at a ceremony on Oct. 15 at the Gladstone Institutes in San Francisco.

A stem cell trifecta for teeth research

It was a tooth trifecta among stem cell scientists this week. At Tufts University School of Medicine, researchers made an important advance in the development of bioengineered teeth. The current standard for tooth replacement is a dental implant. This screw-shaped device acts as an artificial tooth root that’s inserted into the jawbone. Implants have been used for 30 years and though successful they can lead to implant failure since they lack many of the properties of natural teeth. By implanting postnatal dental cells along with a gel material into mice, the team demonstrated, in a Journal of Dental Research report, the development of natural tooth buds. As explained in Dentistry Today, these teeth “include features resembling natural tooth buds such as the dental epithelial stem cell niche, enamel knot signaling centers, transient amplifying cells, and mineralized dental tissue formation.”

Another challenge with the development of a bioengineered tooth replacement is reestablishing nerve connections within the tooth, which plays a critical role in its function and protection but doesn’t occur spontaneously after an injury. A research team across the “Pond” at the French National Institute of Health and Medical Research, showed that bone marrow-derived mesenchymal stem cells in the presence of a nerve fiber can help the nerve cells make connections with bioengineered teeth. The study was also published in the Journal of Dental Research.

And finally, a research report about stem cells and the dreaded root canal. When the living soft tissue, or dental pulp, of a tooth becomes infected, the primary course of action is the removal of that tissue via a root canal. The big downside to this procedure is that it leaves the patient with a dead tooth which can be susceptible to future infections. To combat this side effect, researchers at the New Jersey Institute of Technology report the development of a potential remedy: a gel containing a fragment of a protein that stimulates the growth of new blood vessels as well as a fragment of a protein that spurs dental stem cells to divide and grow. Though this technology is still at an early stage, it promises to help keep teeth alive and healthy after root canal. The study was presented this week at the National Meeting of the American Chemical Society.

Here’s an animated video that helps explain the research:

Stem cell summer: high school students document internships via social media, Part 3

Today we share our third and final pair of social media awards from CIRM’s 2018 SPARK (Summer Program to Accelerate Regenerative medicine Knowledge) program, a 6-12 week summer internship program that provides hands-on stem cell research training to high school students throughout California.

AnthonyTan

CIRM SPARK 2018 Best Instagram Post winner by Caltech SPARK intern Anthony Tan

As part of their curriculum, the students were asked to write a blog and to post Instagram photos (follow #cirmsparklab) to document their internship experiences. Several CIRM team members selected their favorite entries and presented awards to the winning interns at the SPARK Student Conference earlier this month at UC Davis.

The two winners featured today are Caltech SPARK student, Anthony Tan – a senior at John A. Rowland High School – one of the Instagram Award winners (see his Instagram post above) and UCSF SPARK student Gennifer Hom – a senior at Ruth Asawa School of the Arts – one of the Blog Award winners. Read her blog below. (To learn about the other 2018 social media winners, see our previous blog posts here and here.)

Best Blog Award:
My SPARK 2018 summer stem cell research internship experience
By Gennifer Hom

genniferhom

Gennifer Hom

When I was seven, I remember looking up at the stars, I stared hard at the moon through my car window, thinking that it only revolves around me as it followed me home. I later learned in class that we rotate around the sun, as gravity holds the spinning planets in place, simultaneously, the moon revolves around the earth. Out of nowhere, I abruptly felt an actual light bulb switched on above my head once I learned how day and night came. Overcome with curiosity,“ Where did the Big Bang take place? When will my Big Bang happen?”

My interest dissipated as I entered into my high school career. I was struck with incoherence, an inconsistency to my thoughts, as I leaned my shoulder against the wall—for I had already decided to let my fatigue to take over. I felt lacking, unconfident in my abilities even to solve a simple balance chemical equation in chemistry class. Science was not my forte. I could never see myself working in a lab setting.

Still, a spark within me still held onto that childhood curiosity of mine. I remember sitting on the bus on my way to school reading about stem cells, which were fascinating to me. We can use these little cells for so many scientific research.

My Big Bang unfolded when I was accepted into the UCSF SEP internship program. I
studied the human-specific population of cortical neural stem cells and evaluated the signaling mechanisms that govern the formation of their identity. Through my performance, I am also contributing to this phenomenal study, helping my community by potentially providing information to help cure mental illnesses. At times, the results of our data did not come out as we wanted it to be. The staining went wrong, and the images were lacking. I would have to repeat the experiment or troubleshoot on the spot continually. However, it’s all a learning process. Even if I do get beautiful image stainings, I still need to repeat the experiments to confirm my results.

Learning was not the only side that is needed under this program. CIRM encouraged us to share our internship experiences on social media. I posted once a week on my studies, what I’ve learned, and how I could teach my viewers about this new research I am performing. I remember in one of the first few meetings we had, where we had to share our research with our peers, “ I can actually understand your studies,” a friend of mine claimed.

I felt powerful, in a sense, that I was able to communicate my knowledge to others to help them understand and teach my study. When I talk to my family and friends about my summer, I feel confident in my ability to comprehend these complex ideas. I could see myself researching, engineering, and fighting for a solution. I want to find the best form of gene therapy, and map each neuron of the brain. Through this two month program, science has become a new passion for me, a cornerstone of my new academic pursuits. It strengthened my theoretical knowledge and gave me an experience where I witnessed the real world laboratory setting. Not only did I learn the fundamental techniques of immunohistochemistry and microscopy, but I was able to receive encouraging advice from the scientists in the Kriegsteins lab and especially my mentor, Madeline Andrews. The experience in a lab comforted me by the idea of the never-ending changes that lured me to a world of thought and endless potential.

How Blockchain Can Increase Accessibility to Stem Cell Therapy

How-Blockchain-Can-Increase-Accessibility-To-Stem-Cell-Therapy-nuv2rsxjt44hfzhay6m2muc596iyxa6z2hckijv6ei

Photo courtesy of BTCManager

The revolution has arrived. Believe it or not, we are living in a world where artificial intelligence, virtual reality, and stem cell therapies are no longer concepts of science fiction, but are realities of our everyday life. While the development of these things may appear to be in their infancy, it’s undoubtedly true that they each hold a unique opportunity for science to unlock cures to diseases like ALS, Sickle Cell disease, Alzheimer’s and Duchenne’s Muscular Dystrophy.

What is equally true however, is despite the fact that these opportunities are on the horizon, on a global scale there are still significant barriers to accessing clinical trials and quality medical care.

So how do we address this?

Well, according to a company called Stem Cell Project – we need to get creative.

This new Japan-based company set out to create the blockchain-enabled Virtual Clinic, fully equipped with AI technology, diagnostic tools, and its own native currency, the Stem Cell Coin.

 Issues with Modern Healthcare

Modern healthcare has developed rapidly in the past few decades, but is not without its drawbacks. For many people there’s a degree of difficulty in gaining access to qualified specialists. When you consider basic factors like distance and skill shortage, or larger issues like the lack of universal healthcare, it means the average person is unable to afford the high cost of preventative medical treatments, leading to more than 45,000 deaths per year in the United States alone.

In many first-world countries, birth rates have declined over the decades whilst the general population has continued to age. Not only has this has increased the need for specialists in fields treating diseases of aging, like Cancer and Alzheimer’s, but it also means we need to accelerate our efforts to keep up with the growing population.

Using Blockchain to Access Health Records

While many hear the word blockchain and think of cryptocurrencies, it also allows for an ultra-secure means by which patients can interact with healthcare professionals without worrying if malicious third-parties can access their most sensitive personal data. It is for this reason that Stem Cell Project decided to use the groundbreaking technology in their Virtual Clinic.

“Patients are increasingly aware of how their data is being used and who is allowed to access it,” explained Stem Cell Project’s founder Shuji Yamaguchi in a news release. “We therefore wanted to find a solution that was highly secure. Having a patient’s trust is, in many ways, the first step to mass adoption for Stem Cell Coin.”

Beyond that, the platform also ensures patients have access to a decentralized and unchangeable health record. Something which to date has never been fully implemented by a large-scale healthcare organization such as the one backing Stem Cell Project.

Opening the Path to Healthcare Equality

As Stem Cell Coin’s vision continues to be rolled out, a number of complementary applications will also be developed to support the Virtual Clinic. Among these, digital initiatives such as pathological and diagnostic imaging systems have the potential to further build upon the notion of a decentralized, universally-accessible healthcare ecosystem.  Moreover, the ability to pay for stem cell treatment via Stem Cell Coin will allow people to pay and travel for therapy regardless of whether their country exerts strict capital controls. The best example of this is China, where even its wealthy citizens are unable to travel to places like the United States of America and Europe for treatment, as the current cost for stem cell therapy ($10,000 – $50,000) exceeds the limits imposed by their government on how much Yuan can be taken abroad.

Counterfeit drugs and treatments could become easier to spot:

Based on reports from the World Health Organization (WHO), the value of the counterfeit drug market is $200 billion annually. In fact, they estimate 80% of the counterfeit drugs that are consumed in the United States come from overseas. Furthermore – they believe that 16% of counterfeit drugs contain the wrong ingredients, and 17% contain the wrong levels of necessarily ingredients. Not only does this undermine the research and scientists, who are actively looking for treatments by following an established protocol, but the financial burden families and patients are enduring to have access to these drugs is considerably high – especially given that WHO reports that 30% of the counterfeit drugs that are available don’t contain any active ingredients whatsoever. A blockchain-based system would ensure a chain-of-custody log, tracking each step of the supply chain at the individual drug/product level.

Results from clinical trials could become more transparent:

It is estimated that 50% of clinical trials go unreported, and investigators often fail to share their study results. This has created crucial safety issues for patients and knowledge gaps for healthcare stakeholders and health policymakers. Some say, blockchain-enabled, time-stamped immutable records of clinical trials, protocols and results could address the issues of fraudulent outcome reporting, data snooping and selective reporting, thereby reducing the incidence of fraud and error in clinical trial records. Furthermore, blockchain-based systems could help drive unprecedented collaboration between participants and researchers for innovative research projects.

 As new projects such as Stem Cell Coin are able to increase access to regenerative medicine, not only will distance or income cease to determine health outcomes, but we might even be able to address other issues plaguing the healthcare industry.

 

 

 

A brief history of the Stem Cell Agency

On Wednesday, August 15 the California State Assembly Select Committee on Biotechnology held an informational hearing on CIRM as part of its mission of ensuring the legislature is up to date and informed about the biotech industry in California. The committee heard from CIRM’s President and CEO Dr. Maria T. Millan and the Vice Chair of our Board, Senator Art Torres (Ret.); two of CIRM’s Patient Advocates (Pawash Priyank and Don Reed) and Dr. Jan Nolta, the Director of the Institute for Regenerative Cures at UC Davis.

The final speaker was David Jensen, whose California Stem Cell Report blog has charted the history of CIRM since its inception. At CIRM we know that not everyone agrees with us all the time, or supports all the decisions we have made in the years since we were approved by voters in 2004, but we do pride ourselves on being open to a thoughtful, vigorous debate on all aspects of stem cell research. David’s presentation to the committee was nothing if not thoughtful, and we thought you might enjoy reading it and so we are presenting it here in its entirety.

For those who prefer to watch than read, here is a video of the entire hearing:

https://www.assembly.ca.gov/media/assembly-select-committee-biotechnology-20180815/video

California’s Stem Cell “Gold Rush:” A Brief Overview of the State’s $3 Billion Stem Cell Agency
Prepared testimony by David Jensen, publisher/editor of the California Stem Cell Report, before the Assembly Select Committee on Biotechnology, Aug. 15, 2018
I was in Mazatlan in Mexico in the fall of 2004 when I first heard about the creation of
California’s stem cell agency. I was reading the Wall Street Journal online and saw a headline that said a new Gold Rush was about to begin in California — this one involving stem cells instead of nuggets.

“Holy Argonauts,” I said to myself, using the term, of course, that refers to the tens of thousands of people who rushed to the California gold fields in 1849. I wanted to know more about what was likely to happen with this new stem cell gold rush.

Today, nearly 14 years later, I still want to know more about the California Institute for
Regenerative Medicine or CIRM, as the agency is formally known. But I can tell you that certain facts are clear.

Borrowing and Autonomy
The agency is unique in California history and among the states throughout the nation. It is the first state agency to fund scientific research with billions of dollars – all of it borrowed. At one point in its history, it is safe to say that the agency was the largest single source of funding in the world for human embryonic stem cell research.

The agency operates with financial and oversight autonomy that is rare in California government, courtesy of the ballot initiative that created it. But that measure also proved to be both a blessing and a curse. The agency’s financial autonomy has allowed it to provide a reasonably steady stream of cash over a number of years, something that is necessary to sustain the long-term research that is critical for development of widely available treatments.

At the same time, the ballot measure carried the agency’s death warrant — no more money after the $3 billion was gone. Cash for new awards is now expected to run out at the end of next year. Over its life, the agency has had a national and somewhat more modestly global impact, both as a source of funding and international cooperation, but also in staying the course on human embryonic stem cell research when the federal government was backing away from it.

Beyond that, the stem cell agency is the only state department whose primary objective is to produce a marketable commercial product. In this case, a cure or treatment for afflictions now nearly untreatable.

Finally, I am all but certain that CIRM is the only state agency that takes back money when a project winds up on the rocks. By the end of last month, that figure totalled in recent years more than $34 million in two big categories of awards. This sort of cash recovery is not a practice that occurs with federal research dollars. With CIRM the money goes back into the pot for more research aimed at treating horrible afflictions.

Evaluations of the Research Effort
Nonetheless the agency has hit some shoals from time to time. In 2010, the agency’s governing board commissioned a $700,000 study of its efforts by the prestigious Institute of Medicine. Two years later, the IOM reported to CIRM that it had some significant flaws.

The IOM study said that the agency had “achieved many notable results.” But it also
recommended sweeping changes to remove conflict of interest problems, clean up a troubling dual-executive arrangement and fundamentally change the nature of the governing board.

The report said,“Far too many board members represent organizations that receive CIRM funding or benefit from that funding. These competing personal and professional interests compromise the perceived independence of the ICOC (the CIRM governing board), introduce potential bias into the board’s decision making, and threaten to undermine confidence in the board.”

The conflict issues are built in by the ballot measure, which gave potential recipient institutions seats on the 29-member governing board. Indeed, in 2017, the last time I calculated the correlation between the board and awards, roughly 90 percent of the money given out by CIRM had gone to institutions with ties to members of the governing board.

About two months after the IOM presented its report, the CIRM board approved a new policy that bars 13 of its 29 members from voting on any grants whatsoever to help deal with questions concerning conflicts of interest on the board.

Other studies about the agency’s performance resulted from a 2010 law in which the legislature modified the initiative to require triennial performance audits that would be paid for by the agency itself. The requirement specifically excluded “scientific performance” from the audit.

The first audit results came in 2012 and contained 27 recommendations for improvement. The most recent performance audit came last spring. The audit firm, Moss Adams, recommended improvements in the areas of private fund-raising, retention of staff and better utilization of board members. The board was told that the agency had made “incredible progress” and that the auditors “usually see a lot of good things.”

The Story of CIRM 2.0
In recent years the agency has been on a self-improvement regime. The effort began in 2014 and was dubbed CIRM 2.0 — a term that was originally coined by a stem cell researcher at UC Davis.

The new direction and emphasis was described by the agency as “radical.” It was aimed at improving speed, efficiency and innovation. And it seems to have largely succeeded.
In 2014, it took almost two years for a good idea to go from application to the final funding stage. The goal was to shorten that to 120 days. Delays in funding are of particular concern to businesses, often for cash flow reasons, but they also mean delays in actually developing a treatment.

This week, the agency said the cash delivery figure now stands at less than 90 days for clinical awards and about 120 days for translational awards.

In 2014, the agency was participating in nine clinical trials, the last stage before a treatment is certified by the federal government for widespread use. Today the agency is involved in 49. In 2014, about 50 patients were involved in those trials. Today the figure is more than 800.

One of the more interesting aspects of CIRM 2.0 marked a departure from what might be called an academic pass-fail approach to the “final exam” for applications from scientists. Instead, CIRM is engaged in a more partner-oriented approach that can be found in some businesses.

Instead of flatly failing an application that is not quite ready for prime time, the idea is to coach applicants along to help bring them up to approval level. Today the agency can count 30 applications that won approval through that process. All of which is work could have slipped away in the more distant past.

CIRM and the Biotech Biz
CIRM is now much more engaged with industry than during its earlier years, when it drew bitter criticism from some business executives. Engagement with biotech firms is critical to bringing a treatment to the public. CIRM is not in the business of actually manufacturing, marketing and selling products. That is a matter left to the private sector.

One reason for closer business connections involves maturation of the work in the field, which has brought research closer to reality. But it is also due to a different focus within the agency as top management has changed.

One of the more difficult areas involving stem cell research and likely treatments is their cost. It is rare to hear researchers or companies talk forthrightly in public about specific dollar amounts. But the cost of drugs and treatment are high visibility matters for patients and elected officials. And estimates of stem cell treatments have run up to at least $900,000.

In 2010, the California legislature moved to help assure affordability by requiring grantees to submit affordable access plans with the caveat that the agency could waive that requirement. How that will ultimately play out as actual products come into the marketplace is yet to be determined.

The Public Policy Questions
A number of significant public policy questions surround the California’s stem cell program involving its creation and execution. They include:
● Is a ballot initiative the best way to approach research and create new state programs?
The initiative is very difficult to alter when changes are needed or priorities change. .
● Does the state have higher health priorities, such as prenatal health care, than supplying
researchers with cash that they could well secure from other sources?
● Is borrowing money to finance the research the best way to go about it? The interest
expense raise the total cost of a $20 million research award to $40 million.
● Should executives of potential recipient institutions serve on the board that awards their employers hundreds of millions of dollars?

This is just a short list of some of the policy matters. Other questions can and should be asked in the wake of the agency’s nearly 14 years of work.

Lives Saved but No Widespread Therapies
Returning to our earlier list of the clear facts about CIRM, another fact is that lives have been saved as the result of clinical trials that the agency it has helped to finance. The youngster from Folsom mentioned earlier in this hearing is one of a number of cases.

That said, these patients received treatment in clinical trials, which may or may not succeed in producing a commercial product that is available to the general public.

Little doubt exists that the agency has advanced the stem cell field and is building towards a critical mass in California. The burgeoning research program at UC Davis, with $138 million in CIRM funding, is one example. Another is the $50 million Alpha Clinic network aimed at creating powerful collaboration within institutions and throughout the state. In addition to Davis, UC San Francisco, UCLA, UC Irvine, UC San Diego and the City of Hope in the Los Angeles area are all part of the Alpha network.

Nonetheless, CIRM has not yet backed a stem cell treatment that is ready for widespread use and fulfilled the voter expectations from 2004 that stem cell cures were right around the corner.

The agency itself also has something of a deadline that is right around the corner in political and scientific terms. Backers of the agency are hoping for another ballot initiative in November 2020 that would pump $5 billion into the program and stave off its slow demise as research winds down. Development of a stem cell treatment that would resonate with voters would be an invaluable development to encourage voters to continue this unique experiment — even if California’s stem cell gold rush does not quite measure up to the dramatic events of 169 years ago.
#######################

3D printed neuronal networks are an important step forward in treating spinal cord injury

Screen Shot 2018-08-20 at 9.56.34 AM

3D printed live neuronal cells. Image courtesy of the University of Minnesota.

Approximately 300,000 people in the United States live with spinal cord injury (SCI), and 17,000 new cases are reported every year. With no cure, the primary treatment option for people with SCI is rehabilitation with a physical therapist combined with medications to control the pain. Given the relatively permanent nature of these injuries, a new study conducted by Dr. Michael McAlpine and Dr. Ann Parr’s groups at the University of Minnesota is particularly exciting. These scientists have developed a 3D-printing technique to generate a network of neuronal cells in the lab, which they hope will be useful to treat patients with long term SCI. This is the first instance of printing and differentiating neuronal stem cells in a lab. Let’s take a look at how they did it!

The investigators started with induced pluripotent stem cells derived from adult cells (ex. blood, skin etc…), which were then used to bioprint the neurons of interest. They not only printed neurons, but also neuronal support cells called oligodendrocytes, which are responsible for ensuring that neurons can transmit messages efficiently. The uniqueness of their approach lies in their printing process, where the cells were printed in the context of a silicone mold. The silicone “guide” promoted neuronal differentiation as well as provided a scaffold for the scientists to spatially organize the architecture of the cells they generated. Both spatial organization and the presence of the neuronal support cells is particularly important because previous studies have shown that while injecting rodents with neural stem cells has improved SCI, the longevity of these results was compromised by a lack of support system for the injected cells. Therefore, the ability to generate both a functional cell type as well as a spatially accurate structure is important to make this neuronal printing system relevant for treating patients.

To confirm that printed cells were functional, the investigators used calcium flux assays, which demonstrated that the neuronal networks generated were able to communicate with each other. Not only were the cells healthy and functional, but their viability was exceptional: 75% of the cells stayed alive, which is remarkable for cells printed in a laboratory.

While there is still a long way to go before this type of treatment can used to treat SCI in humans, the potential for helping people with long term spinal cord injury is significant. Dr. Parr states:

“We’ve found that relaying any signals across the injury could improve functions for the patients. There’s a perception that people with spinal cord injuries will only be happy if they can walk again. In reality, most want simple things like bladder control or to be able to stop uncontrollable movements of their legs. These simple improvements in function could greatly improve their lives.”

The possibility of implanted neuronal stem cells being effective to treat SCI is also being investigated with the CIRM-funded Asterias trial. To check out more information about this work, read our blog post here and the clinical trial details here.

Stem cell stories that caught our eye: 3 blind mice no more and a tale of two tails

Stem cell image of the week: The demise of Three Blind Mice nursery rhyme (Todd Dubnicoff)
Our stem cell image of the week may mark the beginning of the end of the Three Blind Mice nursery rhyme and, more importantly, usher in a new treatment strategy for people suffering from vision loss. That’s because researchers from Icahn School of Medicine at Mount Sinai, New York report in Nature the ability to reprogram support cells in the eyes of blind mice to become photoreceptors, the light-sensing cells that enable sight. The image is an artistic rendering of the study results by team led Dr. Bo Chen, PhD.

Aug16_2018_BoChen_MullerGlia_Eye3930249103

An artist’s rendering incorporates the images of the Müller glia-derived rod photoreceptors. Image credit: Bo Chen, Ph.D.

The initial inspiration for this project came from an observation in zebrafish. These creatures have the remarkable ability to restore vision after severe eye injuries. It turns out that, in response to injury, a type of cell in the eye called Muller glia – which helps maintain the structure and function of the zebrafish retina – transforms into rod photoreceptors, which allow vision in low light.

Now, Muller glia are found in humans and mice too, so the research team sought to harness this shape-shifting, sight-restoring ability of the Muller glia but in the absence of injury. They first injected a gene into the eyes of mice born blind that stimulated the glia cells to divide and grow. Then, to mimic the reprogramming process seen in zebrafish, specific factors were injected to cause the glia to change identity into photoreceptors.

The researchers showed that the glia-derived photoreceptors functioned just like those observed in normal mice and made the right connections with nerve cells responsible for sending visual information to the brain. The team’s next steps are to not only show the cells are functioning properly in the eye and brain but to also do behavioral studies to confirm that the mice can do tasks that require vision.

If these studies pan out, it could lead to a new therapeutic strategy for blinding diseases like retinitis pigmentosa and macular degeneration. Rather than transplanting replacement cells, this treatment approach would spur our own eyes to repair themselves. In the meantime, CIRM-funded researchers have studies currently in clinical trials testing stem cell-based treatments for retinitis pigmentosa and macular degeneration.

A tale of two tails: one regenerates, the other, not quite so much (Kevin McCormack) One of the wonders of nature, well two if you want to be specific, is how both salamanders and lizards are able to regrow their tails if they lose them. But there is a difference. While salamanders can regrow a tail that is almost identical to the original, lizard’s replacements are rather less impressive. Now researchers have found out why.

081518_LR_regeneration_inline_730

In these fluorescence microscopy images, cross sections of original lizard and salamander tails (left) show cartilage (green) and nerve cells (red). In the regenerated tails (right), the lizard’s is made up mostly of cartilage, while the salamander also has developed new nerve cells. Image: Thomas Lozito

The study, published in the Proceedings of the National Academy of Sciences, shows how a lizard’s new tail doesn’t have bone but instead has cartilage, and also lacks nerve cells. The key apparently is the stem cells both use to regenerate the tail. Salamanders use neural stem cells from their spinal cord and turn them into other types of nervous system cell, such as neurons. Lizards neural stem cells are not able to do this.

The researchers, from the University of Pittsburgh, tested their findings by placing neural stem cells from the axolotl salamander into tail stumps from geckos. They noted that, as those tails regrew, some of those transplanted cells turned into neurons.

In an interview in Science News, study co-author Thomas Lozito says the team hope to take those findings and, using the CRISPR/Cas9 gene-editing tool, see if they can regenerate body parts in other animals:

 “My goal is to make the first mouse that can regenerate its tail. We’re kind of using lizards as a stepping-stone.”