CRISPR, the Cancer Question and the California Stem Cell Agency: $13.5 Million Investment in Eight Projects

CRISPR was in the news this week, and it wasn't about how you like your French fries cooked.

CRISPR, for those of you who don't know already, is a relatively easy way to edit genes. The technique is used in at least eight research projects backed by the California stem cell agency, totalling about $13.5 million.

What made CRISPR generate the headlines was research -- as Business Insider reported -- that the "blockbuster gene-editing tool has been linked to cancer." The assessment was described as hype by some scientists.

Paul Knoepfler, the peripatetic stem cell blogger and researcher at UC Davis, explored the implications of the findings in an item earlier this week. He wrote,

"To say that CRISPR-Cas9 gene editing might 'cause cancer' seems premature to me so there probably were and are better ways for people to phrase the big-picture meaning of these new papers and others like them that may pop up in the future. However, to be clear safety is crucial, so this is an important development and risks of any potential therapy including gene editing-based approaches should be carefully weighed against potential benefits as trials are designed and then progress."

The California Stem Cell Report asked the agency, which monitors the research it funds, for a list of its projects involving CRISPR. Here is what the agency provided, including the disease focus, principal investigator and grant number.

• Sickle cell disease, $4.5 million, Childrens Hospital Oakland Research Institute, Mark Walters, TRAN1-09292
• Muscular dystrophy, $2.2 million, UCLA, April Pyle, DISC2-08824
• Vision loss, $232,200, UC San Diego, Karl Wahlin, DISC1-08683
• Neurological disorders, $1.9 million, Parkinson's Institute, Birgitt Schuele, DISC2-09610
• Blood disorders, immune disease, $984,228, Stanford, Rosa Bacchetta, DISC2-09526
• Blood disorders, $1.5 million, UCLA, Caroline Kuo, DISC2-10124
• Cystic Fibrosis, respiratory disorders, $2 million, Stanford, Matthew Porteus, DISC2-09637
• Blood Cancer, cancer, $235,800, UC Berkeley, Jacob Corn, DISC1-08776

Not a Dr. Ruth Explainer: California Stem Cell Agency's FAQ

Looking for a reasonably straight forward primer on the $3 billion California stem cell agency, a state program that is unique in California history and now in its 13th year of life? 

The agency, formally known as the California Institute for Regenerative Medicine (CIRM), has compiled an FAQ (frequently asked questions) list which is available on its web site. Obviously, some of the material is colored by agency's own perspective, but the basic facts are there in one handy document.

The questions deal with such things as "when will there be cures," "shouldn't private industry fund stem cell research" and "what happens when the money runs out."  It's not exactly a Dr. Ruth's guide to all things CIRM, but many may find the document helpful.

Fire, Fury and $5 Billion: A Mini Preview of a Ballot Campaign for the California Stem Cell Agency

California's stem cell research effort, which is pinning its survival hopes on a proposed $5 billion bond measure in a couple of years, was slammed in a national publication last week as a "multi-billion dollar money suck."

The column in the conservative magazine National Review, which has about 90,000 circulation and a significant online presence, was a tiny preview of the fire and fury that is likely to erupt around the likely pitch to California voters in 2020 to give more cash to the agency.

Formally known as the California Institute for Regenerative Medicine (CIRM), the agency was created by a ballot initiative in 2004 and backed with $3 billion in state funds. It expects to run out of money for new awards by the end of next year.

Wesley J. Smith, a longtime critic of the agency, wrote in the National Review piece,

"The mendacious (2004) campaign promised Cures! Cures! Cures! with embryonic stem cells and therapeutic human cloning — even promising that disabled children would get out of their wheel chairs and walk. Good grief, campaigners also claimed that the money earned from all the coming cures would reduce California’s health-care budget.

"Some $2 billion later, none of it came to pass. Tens of millions were spent on a fancy-dancy building. Conflicts of interested have abounded. But the supposed point of the CIRM was not achieved. There have been extremely few human trials with embryonic stem cells — mostly dealing with eye conditions — and not all were CIRM-funded."

It is fair to say that Smith's characterizations omit much information about what CIRM calls its value proposition. Nonetheless, his points are likely to resonate with a substantial portion of California voters, who have seen little mainstream media coverage of CIRM. 

Even the institutions and recipients of multi-million dollar research awards regularly fail to note CIRM's contributions in their news releases about state-backed scientific discoveries. (See here and here.)

As of today, the agency has invested in 49 clinical trials, the last stage before a therapy is approved for widespread use. A discovery or treatment that would captivate the public could emerge from those trials between now and the election in November 2020. Meanwhile, given the nature of today's financially struggling media and limited science coverage, the agency and its backers are likely to find it tough to break through the news clutter and convince voters to cough up more cash.   

'Spontaneity' Live: A Powerful, Cyberspace PR Tool for California's Cash-Strapped Stem Cell Program?

Jeanne Loring, right, on a Scripps Research Institute
Facebook Live event last week.   Click here to go to the video. 

Stem cell researchers rarely have a chance to talk directly about their work to thousands of people at a time, including those in the farthest reaches of the globe.

But Jeanne Loring at the Scripps Research Institute did it last week. The California stem cell agency did it last month with Stanford researcher Gary Steinberg.  And it could well be that the technique that they used will emerge as a critical tool in the effort to stave off the death of the $3 billion, stem cell program. The end could come as early as 2020 if agency supporters fail that year to win voter approval of $5 billion more for the program.

The medium in use by Loring and the agency is something called "Facebook Live."  It is a live streaming service that allows viewers to ask questions and comment during a webcast conducted by researchers or stem cell research advocates.  It is considerably more compelling than pre-recorded videos, says Forbes magazine, which reports that presentations on Facebook Live are viewed for three times as long as a static video. The thinking is that the interactive connection and the initial live presentation -- with its informality, spontaneity and lack of predictability --  are more interesting than your usual, pre-recorded sessions.

Facebook Live has been around since 2016.  but has rolled out slowly. According to a Google search this past weekend, only a handful of stem cell-connected enterprises have taken advantage of it. (See a few below.)

Viral Boost for the California Stem Cell Message

In its presentation last month, the stem cell agency started off with about 80 viewers. By the time of this writing the number of views of the video had skyrocketed to more than 6,800. Loring's presentation now stands at 1,600. Her number grew by 100 as this article was being written. That viral strength likely surpasses many static offerings in print coverage or conventional electronic news, which are largely onetime shots.

(The agency, on the morning following this posting, filed an item on its blog, hailing the success of the program. The item said, "We had an amazing response from people during the event and in the days since then with some 6,750 people watching the video and almost 1,000 people reacting by posting a comment or sharing it with friends. It was one of the most successful things we have ever done on Facebook so it’s not surprising that we plan on doing many more Facebook Live ‘Ask the Expert’ events in the future.")

One might ask: Why is the impact of this single Facebook event important in terms of a stem cell ballot campaign?

In recent years, the stem cell agency has slipped out of the public eye and is hard-pressed to attract widespread media attention, a situation that is commonplace for most state government departments. The agency's "value proposition" is not well understood, say officials at the agency, formally known as the California Institute for Regenerative Medicine (CIRM). 

To win approval of a proposed $5 billion bond measure in November 2020, however, CIRM will need strong support for its efforts, which have so far failed to deliver on the public's expectations that miraculous stem cell therapies are right around the corner. Those hopes were raised more than 13 years ago during the campaign that created the stem cell agency. Today its funds are running out. Cash for new awards is  expected to vanish by the end of next year.

Selling Hope to Half of California Families

Nonetheless, one of CIRM's notable products is hope -- not to mention 49 clinical trials that could lead to therapies for deadly diseases and widespread afflictions ranging from cancer to urinary incontinence.

In 2004, backers of the stem cell ballot measure declared that "medical problems that could benefit from stem cell research affect 128 million Americans including a child or adult in nearly half of all California families."

Reaching those California families is the key to unlocking their votes on behalf of the stem cell program. Facebook -- notably and coincidentally -- reaches nearly half of the Internet users  in California.

Using Facebook Live, or rival services, may well be the most effective way to connect with those important voters, especially with the help of the patient advocates who have been heavily involved with the agency. They bring the personal stories that resonate with voters and create an emotional appeal that is likely to trigger a favorable vote for more billions.

More services like Facebook Live will probably arise in the next 12 months. But Facebook has an advantage: the huge number of its users and an established Internet base that includes the patient advocate community and its organizations.

Writing on Forbes about business applications of Facebook Live, Steve Olenski said:

"Live video comes with a generous helping of transparency. Your influencer's voice will ring truer in a live conversation with fans than it does in a blog post. Viewers can engage with your product or service and the influencer in open conversation handled in real time.

"If you're looking for a compelling way to build trust with your audience, a live video is a great place to start."

Here are links to a few Facebook Live events involving stem cell-related matters: Difference between gene therapy and stem cell therapy, CAR T-Cell Therapy for Non-Hodgkin Lymphoma, Gene Therapy for Sickle Cell Disease.

Viral Power: California Stem Cell Agency Hits 6K with Cyberspace Event on Stroke Therapy

Here is the Facebook Live event produced by CIRM. The number in the left hand 

corner is not static. It changes as the video is viewed by more persons. 

The $3 billion California stem cell agency last week mounted its first "Ask the Experts" session on Facebook, a look at a stroke therapy that left one patient crying with joy and  researchers "shocked" at the initial, beneficial results.

The Facebook Live event dealt with a stem cell treatment for the most common form of strokes, which claim 750,000 victims annually. It is the leading cause of disability in this country and third leading cause of death.

The webcast at noon last Thursday drew only about 80 viewers, the agency reported. But by late Monday, Facebook statistics showed that it had been viewed more than 6,400 times (more than 6,500 by this morning). The figures demonstrated the viral power of Internet communications in spreading the stem cell agency's message. Not to mention that it could help to stave off the agency's financial demise.

Featured on the webcast were researcher Gary Steinberg of Stanford University, whose work has been supported by $24 million from the agency, and Sonia Coontz of Long Beach, Ca., who said she wept after treatment in the clinical trial as she experienced immediate improvements. Steinberg said his team was "shocked" by the rapidity with which some patients improved from their ischemic strokes.

More than 172 comments were made during the session. Some simply sought more information. Others waxed euphoric. Lisa Bayha Deck, wrote on Facebook,

"I’m a patient of Dr. Steinberg’s and so thankful for his professionalism. He gave me my life back after four strokes and Moyamoya Disease."

The Facebook event was the latest effort by the agency, formally known as the California Institute for Regenerative Medicine (CIRM), to educate the public about the work it is financing. However, the agency expects to run out of cash for new awards by the end of next year. It hopes that voters will provide it with $5 billion more in state bond funding via a ballot measure in November 2020. 

During the event, Lila Collins, a senior scientist at CIRM, provided an overview of key stem cell trials around the country. Kevin McCormack, senior director of communication at CIRM, moderated and produced the session.   

Following the event, McCormack said he thought it went well for an initial effort, although he said he was caught up in the mechanics of handling the session. On Monday, McCormack said, 

"We are going through the stats now and plan on putting together a roundup of views, comments, etc. We are also planning on posting a blog about the event – with answers to questions we didn’t get around to during the hour – so that should be coming in the next few days."

Prior to the webcast, the California Stem Cell Report asked McCormack to elaborate on the agency's Facebook effort. Here is a lightly edited version of that email interview. 

Q: Is this the first such event for CIRM? 

A: It’s the first Facebook Live event we are doing. A few years ago we did a similar series using Google Hangout. We featured a number of our experts in ALS and cancer, heart disease etc. but that wasn’t as easy to do technically. Facebook Live is simpler and because so many more people are on Facebook on a regular basis it will hopefully allow us to reach a wider audience. 

Q: Why is CIRM doing this event? 

A: It’s just part of our outreach efforts to let people know how stem cell research is progressing and the role that CIRM is playing in advancing that. We have been doing similar things for years, reporting back to the people of California on the work we are doing. We do it regularly with in-person patient advocate meetings, and with talks and presentations all around the state so we just wanted to take advantage of this technology to see if we could reach a wider audience.

Q: Will it be saved on the CIRM web site for future viewing?

A: One of the great features of Facebook Live is that it is automatically saved at the end and you can watch them on Facebook again and again. And yes, we’ll be putting links to them on our website but the easiest way to find them is to just go to our Facebook page.

Q: How did this originate?

A: We are always looking for new ways to reach out to a wider audience and let people know about CIRM’s help in advancing stem cell research. We looked at Facebook Live and thought it could be a great tool for us. We are already on Facebook anyway so this was a natural extension.

Q: And, finally, is there anything else you want to say about this event and its significance? 

A: Earlier this year we held a patient advocate event at UC Riverside. It was our first excursion to the Inland Empire and we had a great crowd, more than 100 people showed up on a weekday. But our goal is always to reach as many people as possible, and so we are always exploring new ways, new tools to do that. 

Much as we would like to, we don’t have the staff or budget to travel constantly around the state doing in-person meetings so this is a great way of achieving the same goal in a much more efficient manner. The people of California put a lot of faith in us when they approved $3 billion in funding for stem cell research. As we see that funding really help accelerate the field – we have 49 projects that we funded in clinical trials, we are seeing patients cured of life-threatening diseases – we want to share that news with as many people as possible.

$115 Million Stock Offering by California State-backed Biotech Firm, Forty Seven, Inc.

A California company backed by the state's stem cell agency has announced that it is planning a $115 million initial public offering.

The firm -- Forty Seven, Inc., of Menlo Park -- filed a notice of its plans with the Security and Exchange Commission last Friday. The company has been awarded $15.2 million from the California Institute for Regenerative Medicine (CIRM), as the stem cell agency is formally known.

The company was founded by renown stem cell researcher Irving Weissman of Stanford University, who serves on the Forty Seven board of directors and who has a 9.5 percent equity interest in the firm.

John Carroll of Endpoint News this morning wrote:

"Forty Seven has an interesting past. The 78-year-old Weissman was able to wrangle substantial support for his early research work on CD47 from the California Institute for Regenerative Medicine, even launching early human studies — a rare feat in academic circles. Weissman and former CIRM chief Alan Trounson enjoyed a tight relationship, which extended to Trounson’s appointment to the board of another startup that Weissman had helped found — StemCells, Inc. —shortly after his departure from the agency. And Forty Seven is still getting money from CIRM under its latest $19 million grant."

The company said in its SEC filing,

"We are eligible to receive up to $19.2 million in grants from CIRM and the Leukemia and Lymphoma Society, or LLS, of which $11.6 million has been received through March 31, 2018."

Weissman has received  more than $34 million from the agency, part of the $360 million going to Stanford projects from CIRM, whose 29-member governing board has included a member from Stanford since 2004. Stanford ranks as the No. 1 recipient of funds from the $3 billion California stem cell agency, which is slated to run out of cash for new awards by the end of next year. 

For more on Forty Seven, see here and here.

California Stem Cell Agency and First-of-Kind Fetal Transplant for Fatal Affliction

Nichelle Obar and her daughter, Elianna, at three weeks. NYT photo by Bryan Meltz

A uniquely California medical treatment -- the first of its kind in the world -- won national attention today with reports that it could open the door to similar operations before birth for such diseases as sickle cell and hemophilia.

The therapy was developed by a UC San Francisco researcher who treated "the first patient enrolled in the world’s first clinical trial using stem cells transplanted prior to birth," according to a UCSF news release.

Fetal surgery was also invented in California. And the transplant was backed by $11 million from the state's stem cell agency, a $3 billion enterprise that is unique among states in its size and scope.

Missing from the news, however, was any mention of the agency's multimillion-dollar contribution -- a not insignificant matter since the agency is facing its own financial demise in less than two years. The agency hopes voters will keep it alive and approve $5 billion more for stem cell research in 2020. The agency, however, is laboring under a lack of public awareness for its "value proposition." (See here and here.)

The research is being conducted by Tippi MacKenzie, a pediatric and fetal surgeon who has received a total of nearly $15 million from the agency. Her employer, UC San Francisco, has received $169 million in 81 awards.  Various deans of its medical school have also served on the agency's governing board since the inception of the agency, known formally as the California Institute for Regenerative Medicine (CIRM).  

A spokeswoman for UCSF said omission of the CIRM funding in its news release was not intentional. 

The agency was not mentioned also in a lengthy article on MacKenzie's research in the New York Times this morning. The piece was displayed on the front page of the weekly Science section of the Times, a prestigious position available only 52 times a year.

MacKenzie's work involved a family from Hawaii and their child, who was treated in utero for a nearly always fatal affliction. 

In the article by Denise Grady, the Times reported, 

"Elianna, born Feb. 1 with a robust cry and a cap of gleaming black hair, has a genetic disease that usually kills a fetus before birth. The condition, alpha thalassemia major, leaves red blood cells unable to carry oxygen around the body, causing severe anemia, heart failure and brain damage.

"The transfusions in the womb kept her alive, but only treated her illness. The bone-marrow transplant has the potential to cure it. Whether it will succeed is still too soon to tell.

"Elianna and her mother, Nichelle Obar, were the first patients in an experiment that pushes the limits of fetal therapy, a field already known for its daring."

The Times continued, 

"If the treatment works, it could open the door to using bone-marrow transplants before birth to cure not just Elianna’s blood disease but also sickle cell anemia, hemophilia and other hereditary disorders, some so severe that the prenatal diagnosis may lead parents to end the pregnancy.

"Bone marrow is considered a potential cure because it teems with stem cells, which can create replacements for cells that are missing or defective as a result of genetic flaws."

Asked for comment by the California Stem Cell Report, Maria Millan, president of CIRM and a pediatric surgeon, said in an email, 

“The New York Times picture of Nichelle Obar with her 3 week old daughter Elianna shows us something that’s hard to capture in a billion words.(See photo above.)  Elianna is afflicted with alpha thalassemia major, a fatal condition that usually ends up in death before birth.

"It is extremely gratifying to know that CIRM has been instrumental in supporting Dr. McKenzie’s research to develop a treatment for this severe unmet medical need. Dr. McKenzie’s approach combines surgical advances that allow her to treat the baby while still in the mother’s womb; transplantation with the mother’s blood stem cells provides healthy blood cells that the baby needs to survive. 

"We have supported Dr. McKenzie’s research from the early years when she was a new faculty working out the basic science and immunology in the laboratory and we helped her to develop her clinical plan. Most recently, we have partnered with Dr. McKenzie to bring this research to clinical trials. To see Ms. Obar take their child home from the hospital is encouraging. We know that this is just the beginning. This is what the people of California voted for when they approved Proposition 71. They depend on us to boldly partner with Dr. McKenzie to translate the promise of stem cell treatments to patients with unmet medical needs."

The phase one clinical trial, which is aimed primarily at safety, is scheduled to release its preliminary results by February 2022 and hopes to treat another nine patients. The treatment would then face another two phases of clinical trials for efficacy. 

As for the baby, her mother told the Times, 

“Elianna’s doing great. I’m not disappointed at all. If it works, great. If it didn’t, we’re O.K. with it. We’ll celebrate all the little accomplishments. I’m glad we did it."

Here is a UCSF video on the trial.

Incontinence to Cancer: California Kicks in $26 Million for Stem Cell Research

The California stem cell agency this week awarded more than $26 million in its hunt for treatments for afflictions ranging from cancer and incontinence to osteoporosis and eye disease.

The $3 billion agency's board ratified the five research grants in a 30-minute, telephonic meeting on Thursday with little debate. The applications were previously approved behind closed doors by the agency's out-of-state scientific reviewers.

The largest award -- $12 million -- went to a team at UCLA led by Steven Dubinett for a phase one clinical trial. The agency, formally known as the California Institute for Regenerative Medicine (CIRM), said in a news release:

Steven Dubinett, UCLA photo

"The team is using the patient’s own immune system where their dendritic cells – key cells in our immune system – are genetically modified to boost their ability to stimulate their native T cells - a type of white blood cell - to destroy cancer cells. 

"The investigators will combine this cell therapy with the FDA-approved therapy pembrolizumab (better known as Keytruda) a therapeutic that renders cancer cells more susceptible to clearance by the immune system."

The research application approved this week that would likely have the most widespread application involved urinary incontinence. The $6 million award went to a Stanford team led by Bertha Chen. CIRM said,

Bertha Chen, Stanford photo

"Despite being one of the most common indications for surgery in women, one third of elderly women continue to suffer from debilitating urinary incontinence because they are not candidates for surgery or because surgery fails to address their condition. 

"The Stanford team is developing an approach using the patient’s own cells to create smooth muscle cells that can replace those lost in UI. If this approach is successful, it provides a proof of concept for replacement of smooth muscle cells that could potentially address other conditions in the urinary tract and in the digestive tract."

Here is the full list of winners and links to the summaries of the reviews of their applications and their scores. The review summaries other than the one for Dubinett can be found on a single document, which also contains the review summaries of the 10 rejected applications:

• Steven Dubinett, UCLA, $12 million, application number CLIN2-10784, review summary, title advanced non–small cell lung cancer, co-funding not required but $400,000 provided
• Bertha Chen, Stanford, $6 million, application number TRAN1-10958, review summary, title Autologous iPSC-derived smooth muscle cell therapy for treatment of urinary incontinence, co-funding not required
• Cassandra Calloway, Children's Hospital Oakland Research Institute, application number TRAN2-10990, review summary, target development of a noninvasive prenatal test for beta-hemoglobinopathies for earlier stem cell therapeutic interventions. co-funding not required
• Farhad Parhami, Max BioPharma of Santa Monica, Ca., $1.7 million, application number TRAN1-10937, review summary, title therapeutic development of an oxysterol with bone anabolic and anti-resorptive properties for intervention in osteoporosis, co-funding not required
• Magdalene Seiler, UC Irvine, $4.8 million, application number TRAN1-10995, review summary, title morphological and functional integration of stem cell derived retina organoid sheets into degenerating retina models, co-funding not required

Here is a link to an LA Business Journal story on the award to BioPharma.

A Stem Cell "Nose Job" and Updates on Regulation of Questionable Stem Cell Clinics

Tracking the latest on dubious stem cell clinics, the feds and the implications across the nation can be a bit of consuming task, if you are interested in that sort of thing.

But one Internet site does a pretty good job of keeping up with it. Here is what popped up last week on The Niche, which is based out of UC Davis.

•  A Q&A with a Georgia law professor concerning the federal crackdown on unregulated stem cell clinics. 
• A quick look at activities regarding the state of Washington's new law on stem cell clinics, the failed state regulatory attempt in the stem cell "hot bed" that is Florida plus questions about enforcement of California's new stem cell clinic law. 
• A video of a presentation by an unregulated stem cell clinic which discussed a product described as a  "magic concoction" that is sprayed up the patient's nose.  

Paul Knoepfler is the UC Davis stem cell researcher who produces The Niche and has long written about the dubious clinics that have proliferated across the nation, with the most in California. 

Feds Crack Down on Unregulated 'Stem Cell' Clinics, Including One in California

The Food and Drug Administration has moved to shut down two businesses that offer "stem cell" treatments, including one operation based in California,  following reports that some patients were blinded by treatments.

The lawsuits yesterday were characterized as "historic" by one California stem cell researcher, who has been reporting on unregulated and unproven "stem cell" treatments for several years. 

The firms involved are U.S. Stem Cell in Florida and California Stem Cell Treatment Center and its proprietors, physicians Mark Berman, a cosmetic surgeon, and Elliott Lander, a surgeon and urologist. The California enterprise has locations in Beverly Hills and Rancho Mirage with affiliates in 100 locations around the country.

Michael Hiltzik wrote in the Los Angeles Times,

"The lawsuits are the most aggressive steps yet taken by government regulators against rapidly proliferating stem-cell treatment clinics pitching scientifically unproven therapies to desperate patients, some with terminal illnesses. The lawsuits were filed at the request of the Food and Drug Administration, which last year announced that it would take a stern approach to what it described as the manufacture and use of unlicensed drugs."

Researcher Paul Knoepfler of UC Davis has been raising questions about unregulated and unproven stem cell treatments for a number of years. Writing yesterday on his blog, he called the federal action "historic." He said the suits could mark "a turning point for dealing with the for-profit stem cell clinic problem in the U.S."

Knoepfler also carried on his blog the full statements of the companies denying any wrong doing.

The California stem cell agency has also raised cautionary notes about unregulated treatments. 

Here are links to other stories on the lawsuits, which received national attention: Washington Post, The Associated Press and STAT. The Associated Press was carried by the New York Times and many other outlets online. The Times also carried this story by its own reporters.  Here is a recent column by Hiltzik on the California Stem Cell Treatment Center. The headline on the colum says "Patient lawsuits, federal investigations and a 'virtual' PhD: Inside a would-be stem cell empire." 

Removing the Barriers to Widespread Use of Stem Cell Treatments

If you are really interested in delivering stem cell therapies to the marketplace, the place to be early next month is in Los Angeles at a major, international conference that will examine the bottlenecks that stand in the way of bringing the treatments to the public at large.

The California stem cell agency, which is spending $3 billion to create therapies, says that "key unresolved issues" must be addressed before safe and effective therapies reach the mainstream.

The stem cell agency, formally known as the California Institute for Regenerative Medicine (CIRM), is co-sponsoring the two-day event June 5 and June 6 with the The International Alliance for Biological Standardization.  The session is drawing speakers from around the world. 

Abla Creasey, CIRM photo

Earlier this year, Abla Creasey,  vice president of therapeutics and strategic infrastructure at the agency, said, 

“The field of stem cell research and regenerative medicine has matured to the point where there are over 900 clinical trials worldwide. It is critical to develop a system of effective regulation of how these stem cell treatments are developed and manufactured so patients can benefit from future treatments.”

Her comments appeared on the agency's blog, The Stem Cellar, in an item written by Geoff Lomax, senior officer for CIRM strategic initiatives. Lomax also quoted Martin Pera, a professor at the Jackson Laboratory in Maine and who also directs the International Stem Cell Initiative Genetics and Epigenetics Study Group, and Robert Deans, chief technology officer of Blue Rock Therapeutics, Inc.,  of Cambridge, Mass.

Pera said,

“Participants at this meeting will survey and discuss the state of the art in the development of definitive assays for assessing the safety of pluripotent stem cell based therapies, a critical issue for the future of the field. Anyone active in cell therapy should attend this meeting to contribute to a dialogue that will impact on research directions and ultimately help to define best practice in this sector.”

Deans said,

“I believe standardization will be an increasingly crucial element in securing commercial success for regenerative cell therapies. This applies to all facets of development, from cell characterization and patent protection through safety testing of final product. Most important is the adherence of players in this sector to harmonized standards and creation of a scientifically credible market to the capital community.”

Here is a link for registration.

Golden State's Stem Cell 'Value:' Bubble Boy Disease and Bringing a Therapy to Market

California's $3 billion stem cell agency today performed a double, PR whammy in an effort to create a greater public understanding of the "key role" it can play in the most expensive and critical steps in creating a therapy that is widely available to the public.

The agency's pitch comes as it faces its potential demise in two years unless it is successful in raising more funds for its operations.

Donald Kohn, UCLA photo

The agency's starting point today involved research for cures for an affliction that has received highly visible, albeit intermittent, coverage over the past several decades. The fatal affliction is often referred to as the "bubble boy" syndrome or, more accurately, SCID,  Severe Combined Immune Deficiency.

In this case, it involves UCLA scientist Donald Kohn, a British firm, Orchard Therapeutics, Inc., opening new facilities in California (Menlo Park and Foster City) and a $20 million award. The cash, however, is only a relatively small piece of the state's immune deficiency investment. 

$141 million for immuno deficiencies

Over the years, Kohn's research has been backed by at least $52 million from the taxpayer-financed California Institute for Regenerative Medicine (CIRM), as the agency is formally known. Overall, it has pumped more than $141 million into immune deficiency disorders, not all of which is directly related to SCID. 

Responding to a query, Kevin McCormack, senior director for CIRM communications, said,

"We’re a lot more than just a pretty face you know. We feel we’re helping change the face of medicine."

Or as Maria Millan, president of CIRM, said both in a news release and in an article on the agency's blog, The Stem Cellar: 

"We invest when others are not ready to take a chance on a promising but early stage project. That early support not only helps the scientists get the data they need to show their work has potential, but it also takes some of the risk out of investments by venture capitalists or larger pharmaceutical companies."

She continued, 

"Our funding and partnership has enabled the smooth transfer of Dr. Kohn’s technology from the academic to the industry setting while conducting this important pivotal clinical trial. With our help, Orchard was able to attract more outside investment and now it is able to grow its pipeline utilizing this platform gene therapy approach.”

De-risking stem cell therapies

In biotech, all this is referred often as "de-risking" and helping research advance beyond the "valley of death," the stage at which conventional financing for research becomes exceedingly difficult to secure. Both have been goals of the agency for some time and are part of what Millan refers to as the agency's "value proposition." 

Boosting public recognition of the value created by CIRM is likely to be a key element in winning approval of a proposed $5 billion bond initiative in 2020, seeking more cash for the agency. The agency estimates that it will run out of money for new awards at the end of next year. 

The agency noted the significance of the deal that GlaxoSmithKline(GSK) made last month with Orchard.  Although the agency tends to focus strongly on medical and scientific achievements, today's PR hit had a stronger emphasis on business matters. Without a successful business model, it is unlikely that any CIRM research will reach the general population.

California's key role

CIRM said,

"Under the deal, GSK not only transfers its rare disease gene therapy portfolio to Orchard, it also becomes a shareholder in the company with a 19.9 percent equity stake. GSK is also eligible to receive royalties and commercial milestone payments. This agreement is both a recognition of Orchard’s expertise in this area, and the financial potential of developing treatments for rare conditions."

Mark Rothera, Orchard photo 

The agency quoted the CEO of Orchard, Mark Rothera, as saying,

"The funding and advice from CIRM allowed Orchard to accelerate the development of OTL-101 and to build a manufacturing platform to support our development pipeline which includes 5 clinical and additional preclinical programs for potentially transformative gene therapies."

The GSK-Orchard deal, CIRM said, was "good news for both companies and for the patients who are hoping this research could lead to new treatments, even cures, for some rare diseases. It was also good news for CIRM, which played a key role in helping Orchard grow to the point where this deal was possible."

Alpha Clinic Kickoff: Launch of Capricor Trial for Duchenne in $50 Million California Stem Cell Network

UC Davis this week inaugurated its Alpha Clinic program, part of a $50 million, statewide network created by California's 13-year-old stem cell research agency.

The school kicked off its program with the start of a "HOPE-2" clinical trial for Duchenne muscular dystrophy – a fatal genetic disorder mainly affecting boys and young men. About 200,000 persons worldwide suffer with the affliction. There is no cure. Treatment options are limited.

Craig McDonald
UC Davis photo

The lead trial investigator, Craig McDonald of UC Davis, said in a news release,

"Collaborating with the Alpha Clinic team enables us to capitalize on their research infrastructure and expertise for clinical trials focused on cell-based therapies.

"It complements the skills of UC Davis’ Neuromuscular Research Unit, which is a national leader in conducting Duchenne trials. We believe this unique partnership could be a model for translating stem cell discoveries into meaningful treatments for patients with muscular dystrophy and other serious progressive neurologic diseases.”

The trial will test the safety and efficacy of a therapy developed by Capricor, Inc., of Beverly Hills -- CAP-1002. The state's stem cell agency, formally known as the California Institute for Regenerative Medicine (CIRM), in 2016 awarded the firm $3.4 million, part of a total of $17.8 million that the firm has received from the state. CIRM has also awarded another $7 million to Cedars-Sinai for early development work that led to the creation of Capricor.  

(Here is a link to the summary of the review of the Capricor application, CLIN2-08334, submitted by Deborah Ascheim, chief medical officer at Capricor.)

CIRM governing board member Jeff Sheehy said in 2016,

"This is pretty much a pure CIRM product. They came into our first disease team to develop the product. We've supported two of the three clinical trials. So if this turns out to be a major success, this will be a real feather for CIRM. We've been with them all the way. So I'm optimistic."

Linda Marban, president of the firm, said in a news release that the research is "one of the very few clinical initiatives to focus on helping boys and young men whose ability to walk has been seriously impaired by the loss of muscle function that occurs as Duchenne muscular dystrophy progresses."

Capricor is a publicly traded firm, whose stock closed at $1.32 today. The 52-week high on the stock was $4.25 and its  52-week low 63 cents.

The Alpha Clinics are one of the signature programs of the stem cell agency. In addition to Davis, UC San Francisco, the City of Hope, UCLA, UC Irvine and UC San Diego are part of the network. UC Davis last year received $8 million from CIRM to help create its program. 

A California Scientist's Eight-Year Journey into the Byways of Dubious 'Stem Cell' Clinics

You could call it the "Knoepfler Effect."

It has bounced noticeably around the country in recent months, leading to headlines in the Washington Post, the Atlanta Constitution, the Los Angeles Times and other outlets in Florida, Seattle and elsewhere.

It involves the activities of dubious, so-called "stem cell clinics" -- enterprises once ignored by the mainstream media, the Food and Drug Administration as well as other regulators, including California lawmakers, and much of the established stem cell scientific community.

Not so today. Here is a sampling of the recent news coverage:

• "How ‘stem cell’ clinics became a Wild West for dodgy treatments"
• "Unregulated stem-cell clinics are proliferating across the United States"
• “There's a problem with stem cell therapy in Florida”
• "Patient lawsuits, federal investigations and a 'virtual' PhD: Inside a would-be stem cell empire"

Paul Knoepfler
UC Davis photo 

Over the last several months, these "stem cell" businesses have come under increasing scrutiny by media and regulators. Much of the credit for the attention must go to Paul Knoepfler, a stem cell researcher and blogger at UC Davis. About eight years ago, he began writing -- largely alone and in isolation -- on his blog about the problem. 

He was convinced that the persons lured into the "clinics" were paying large sums for so-called treatments that did not fulfill their promise and that, in fact, could be dangerous. In one case, Knoepfler went undercover -- sort of. He later tangled politely with the leading newspaper in California's state capital about how it was carrying full page ads from an unregulated clinic.

The watershed moment came in 2016 when Knoepfler and Leigh Turner of the University of Minnesota put a number to the matter -- 570 dubious "stem cell" firms nationwide with California leading the nation with 113. That was the key. Readers and regulators like solid numbers. They help focus attention, providing a hook for action and creating a new understanding.  Knoepfler and Turner's peer-reviewed scientific journal piece was the biggest stem cell story in the country that week.

Knoepfler also learned about the media game. He promptly returned media emails and calls and couched his responses in plain English -- "good quotes," as they are known in the trade.

Knoefler persisted even while some of his peers looked disparagingly at his blogging.  Back in 2012, one told Knoepfler that he was "skeptical of scientific social media with its 'twitting and the blobs(cq)'."

In California, however, his work helped to lead to a new law that forces the "stem cell" enterprises to inform their customers more fully about the nature of what might happen to their bodies.

It is a ticklish business to credit a specific individual with triggering a fresh wave of public attention to new and complex issues, such as stem cells and their dubious exploitation. Turner and others have been involved as well and deserve considerable credit. But Knoepfler was at the forefront and did, in fact, take a few arrows for his work.

The California Stem Cell Report asked Knoepfler for his brief thoughts about his stem cell adventures. He replied,

"Some highlights include times when patients decided not to get risky stem cells for themselves or their kids. I also have enjoyed getting to know so many cool people from diverse backgrounds all over the world I’ve only met because of the blog.

"Seeing things like the new California stem cell clinic law sprout up is exciting too, especially as now other states are trying to follow our state's lead it seems and maybe pass even better legislation. I’m also hopeful to have positive impact at the national level such as by somehow working a miracle to get the FDA to do more overall, but we’ll see how that turns out. 

"If that all sounds too cheery, then as my grandma might have said back in the 70s, 'It’s not all peaches and cream.' 

"There have been downsides too like various threats from clinics or their fans. I also feel like at times I’ve stepped in it with something I wrote or said when I could have avoided headaches if I had been wiser. Anyone can do that, but when you do it publicly such as on a blog then it’s got more bite to it. Doing all this stuff has risks to it. But overall it’s been worth it."  

A final note: People often shrug at the likelihood that they can make change in society. Many scientists as well shy from speaking out publicly, surrendering the public arena to snake oil peddlers. But the "Knoepfler Effect" stands as evidence that persistence and first-class work can, in fact, make a real difference in science and public policy. 

California Hits More Than Half-Billion Dollars in Stem Cell Clinical Trials

The stem call agency has an interactive dashboard on its web site, part of which is seen above.

The California stem cell agency this week boosted the number of its clinical trials to 48 -- representing an investment of $553 million -- with the hope of producing its first widely available stem cell therapy and staving off its own demise.

In a 14-minute, telephonic meeting Thursday, directors of the agency ratified three new awards totalling $32 million and increasing its trials from 45. The applications had been approved earlier behind closed doors by the agency's out-of-state reviewers.

The action left the agency, known formally as the California Institute for Regenerative Medicine (CIRM), with $224 million in uncommitted funds, CIRM said in response to a query. The agency was provided with $3 billion when it was created in 2004 by California voters. The $224 million figure could rise $278 million with "recovery" from cancelled grants.

Nonetheless, CIRM expects to run out of cash for new awards by the end of 2019. It is attempting to raise $220 million privately to tide it over until November 2020, the date when voters may be asked to approved an additional $5 billion in bond funding.

Thursday's brief meeting generated no fresh discussion about the financial future of the agency, which is unique in California history and operates with no oversight by the governor or the legislature. Nor was there any discussion of the applications for research funds. 

CIRM said in a news release this morning that while the agency has backed 48 trials, only 42 are active. It has also funded early stage research in 11 additional projects that moved later into the "clinical trial stage" without additional CIRM support. 

The directors made their award decisions Thursday based on a brief CIRM staff presentation and summaries of the reviews of the applications. 

Links to the summaries, the winners and their awards are below. Go to the summaries by clicking on the application number. Updates on the status of CIRM research can also be found as it progresses by searching on the application number.

Sangamo Therapeutics, Inc., of Richmond, Ca., was awarded $8 million to "test a new therapy (phase one/two) for beta-thalassemia, a severe form of anemia (lack of healthy red blood cells) caused by mutations in the beta hemoglobin gene."

The agency said,

Edward Conner
Sangamo photo

"Patients with this genetic disorder require frequent blood transfusions for survival and have a life expectancy of only 30-50 years."

The company, which announced a secondary stock offering of more than $200 million this week, is providing $15 million in co-financing. Its stock closed at $16.75 on Friday. Its 52-week high is $27.50 and its low $4.25. 

The principal investigator is Edward Conner, chief medical officer of the firm, and the application number is CLIN2-11031. 
The company said in a news release that the work also involved Bioverativ.

Stanford University researchers received $12.3 million and provided $2.3 million in matching funds for a a phase one trial for a CAR-T therapy for "patients with B cell leukemias who have relapsed or are not responding after standard treatments, such as chemotherapy."

Maria Millan, president of CIRM, said in the news release,

Crystal Mackall
Stanford photo

“When a patient is told that their cancer has returned it can be devastating news. CAR-T cell therapy is an exciting and promising new approach that offers us a way to help patients fight back against a relapse, using their own cells to target and destroy the cancer.”

The principal investigator is Crystal Mackall and the application number is CLIN2-10846. 

(Here is the link from Stanford on the award. The link was added on April 30 to this item after its initial publication.)

Morton Cowan
UCSF photo

UC San Francisco researchers received $12 million (with no co-funding) for a phase one trial to test a treatment "to restore the defective immune system of children born with severe combined immunodeficiency (SCID), a genetic blood disorder in which even a mild infection can be fatal" and which is often known as "the bubble baby disease."

CIRM said it has"funded two other clinical trials targeting different approaches to different forms of SCID. In one, carried out by UCLA and Orchard Therapeutics, 50 children have been treated and all 50 are considered functionally cured."

The principal researcher is Morton Cowan and the application number is CLIN2-10830.

Weighing California's Stem Cell Trials: An Update from the Golden State's Stem Cell Agency

A sample from the latest information from CIRM on its clinical trial investments. 

California's $3 billion stem cell agency has posted a fresh overview of the 45 clinical trials that it has invested in, ranging from spinal injuries to kidney transplants.

The update is part of the agency's push to better inform the public as well its governing board of the scope and status of its 13-year-old efforts. The clinical trials carry special weight as the agency faces its demise unless it is successful in raising $220 million privately and winning voter approval of a proposed $5 billion bond issue in November 2020.

The Oakland-based agency, formally known as the California Institute for Regenerative Medicine (CIRM), expects to run out of cash for new awards by the end of 2019. Its only funding has been the $3 billion in bonds approved by voters in 2004. The ballot initiative provided no additional source of financing to carry it into the future.

Clinical trials are critical for the agency as it approaches the date when it must ask for more billions. They are the last stage before a therapy is approved for widespread use by the federal government. But even then, a trial can take years. And nine out of 10 proposed, "normal" -- non stem cell -- therapies fail during the clinical trial process, according to studies.  Stem cell trials are so new that their failure rates has not been fully examined.

CIRM is hoping for results in the next year or so that will resonate with voters and lead them to approve additional funding.

The five-page, clinical trial overview sorts the trial information by disease, dollar amount, benefit and date among other things. (See sample of the layout above.) The agency also has additional useful information on its trials on what it calls its clinical trials dashboard, an interactive web page that allows readers to slice and dice the information.

The fresh document on the trials was released as part of the agenda for tomorrow's CIRM meeting during which its governing board is expected to approve $32 million for three additional trials. 

Stem Cell 'Hotbed:' A CIRM Roadshow in Riverside

California's $3 billion stem cell agency took its message of hope for possible therapies to Riverside this week, part of its continuing outreach program that is increasingly taking on additional importance.

Why? Because the agency is scheduled to run out of cash for new awards by the end of next year. It is hoping to raise $220 million to stave off its demise until November 2020 when the plan is to ask state voters to approve an additional $5 billion in funding.

Writing on the agency's blog, Kevin McCormack, senior director of communications for the agency, was enthusiastic. His headline said, 

"A road trip to the Inland Empire highlights a hot bed of stem cell research"

McCormack wrote,

"It was a packed event, with an overflow group watching on monitors outside the auditorium. The questions asked afterwards didn’t just focus on the research being done, but on research that still needs to be done.
"One patient advocate couple asked about clinics offering stem cell therapies for Parkinson’s disease, wondering if the therapies were worth spending more than $10,000 on....
"The visit was a strong reminder that there is exciting stem cell research taking place all over California and that the Inland Empire is a key player in that research, working on projects that could one day have a huge impact in changing people’s lives, even saving people’s lives."

The stem cell agency, formally known as the California Institute for Regenerative Medicine (CIRM), is not exactly a household word among most Californians. Events such as the one in Riverside help to spread the word about its activities to voters who might be considering another funding initiative for the agency. However, these type of CIRM events rarely generate news coverage that can amplify their reach. 

The Riverside event was a case in point. A UC Riverside press release earlier this month led to a four-paragraph item in the Riverside Press Enterprise announcing that the event was upcoming. But no news story has yet emerged from the actual event itself. Indeed, the only news story in the newspaper this month about the benefits of stem cell research involved the Vatican, a Riverside girl and, indirectly, a company, Caladrius Biosciences (formerly Neostem) that was awarded $11.6 million from CIRM. The agency, however, was not mentioned.

Tomorrow, another CIRM event will be held at UCLA to highlight the agency's  $50 million, Alpha Clinic program that brings resources together to focus intensely on stem cell therapies and patient treatment.

Fleshing Out the Details: Inside the California Stem Cell Agency's Fledgling Industry Partnership Program

 California's $3 billion stem cell agency has released details on just what is involved in its new collaboration with industry, giving select companies "direct access" to the hundreds of millions of dollars in research that the state has financed. 

The effort involves creation of "robust data rooms," nondisclosure agreements and licensing templates, among other things, and owes a debt to the agency's moribund, $150 million public-private partnership proposal (ATP3).  The new program is aimed at speeding development of stem cell therapies as the agency faces its possible demise in the next couple of years. 

The California Institute for Regenerative Medicine (CIRM), as the agency is formally known, has dubbed the collaboration as the Industry Alliance Program (IAP). It  already has two partners from the private sector, BlueRock Therapeutics of Cambridge, Mass., and Vivo Capital of Palo Alto, and the agency is looking for more. 

Q & A: Data Rooms and More

Neil Littman, CIRM photo

CIRM disclosed more information about the program in response to questions from the California Stem Cell Report (CSCR). Here is the agency's reply from Neil Littman, CIRM's business development officer. It includes a response to a comment filed last week on the original article by an anonymous reader concerning access to research.

CSCR: "What does 'direct access' to CIRM’s growing stem cell portfolio' mean? Will grantees be asked to share their results with these companies....or will CIRM just give out grantees' proprietary information to these companies?"

Littman:  "CIRM will never share proprietary information without the consent of the awardee and the awardee’s institution. In addition, in order to access non-public information, IAP partners (just like everyone else) will need to execute a confidentiality agreement with the awardee’s institution. 'Direct access' implies CIRM’s role in helping IAP partners navigate CIRM’s large and growing portfolio and facilitating introductions when it is mutually agreed upon by the awardee and IAP partner."

CSCR: "It would be useful to discuss with more specificity this language from the IAP agreements: "...diligence process through template legal agreements, such as non-disclosure agreements and licensing templates, and robust data rooms."

Littman: "What does CIRM mean by diligence process? The term due diligence refers to the process of how a company evaluates technology before making an investment. This is often a lengthy review process where the company evaluates items such as preclinical clinical and clinical data, CMC information, and regulatory correspondence. CIRM will help streamline this process by working with the awardee and awardee’s institution to gather all the information in one place for the collaborator to review (this is commonly referred to as a 'data room').

"Why are template agreements useful to collaborators? The template legal agreements provide standardized language which help save time for both the collaborator and the awardee institution. Many features of the agreements will still need to be negotiated, such as the economics of a specific deal, but the templates serve as a starting point."

Son of ATP3

CSCR: These arrangements appear to be descended from CIRM's ATP3 proposal. How did the partnership program emerge? How did those two companies come to be the first to be involved? 

Littman: "Yes, the IAP is descended from ATP3 and is meant to achieve the same goal: increasing the pull from industry in order to increase the number of partnerships. BlueRock and Vivo Capital were selected for a variety of reasons, including: 1) Demonstrated commitment to advancing stem cell treatments to patients (i.e. they have already made investments in the space) 2) Continued commitment to investing in stem cell programs in the future, 3) They are well capitalized with the ability to invest in CIRM-funded programs."

Text of IAP Agreement

Here is the text of the signed agreement with BlueRock, which was requested by the California Stem Cell Report. The agreement with Vivo is identical.

   California stem cell agency agreement with BlueRock Therapeutics by DavidJensen on Scribd

California's $3 Billion Stem Cell Program Partners with BlueRock and Vivo Capital, Looks for More Industry Collaborators

California's drive to produce a stem cell therapy is ratcheting up a notch with announcement of  two new, global industry partners along with a plan to engage more companies and give them "direct access" to hundreds of millions of dollars in state-funded research.

The California Institute for Regenerative Medicine (CIRM), as the $3 billion state stem cell agency is formally known, said the program represents an opportunity "to bring the most promising stem cell, gene therapy and regenerative medicine programs to market where they can help people with unmet medical needs."

The first two participants are BlueRock Therapeutics of  Cambridge, Ma., with offices in Toronto and New York City, and  Vivo Capital of  Palo Alto, Ca., which has offices in Bejing, Shanghai and Tapei. BlueRock was founded in 2016 with $225 million in backing from Versant Ventures and Bayer AG. Vivo has more than $1.7 billion under management, according to the firm's web site.

In addition to venture capital firms, the agency said its Industry Alliance Program (IAP) is looking for pharmaceutical and biotech partners to give them "direct access to CIRM’s growing stem cell portfolio."

Maria Millan, CEO and president of CIRM, said in a news release,

Maria Millan

"The goal of the IAP is to secure industry partnerships and funding for CIRM’s translational and clinical-stage projects. Our agency provides researchers the initial funding to advance promising projects towards the clinic. Now, we’re going a step further by offering a program that facilitates connections between industry partners and our grantees. These companies can offer the support or additional funding needed to give these promising projects the best chance for success and the best chance of helping patients.”

The stem cell agency is nearing its final days and is looking to fulfill promises to California voters who created it 13 years ago through a ballot initiative. The measure provided $3 billion in state bond funding, but no more. The campaign also generated expectations that stem cell cures were just around the corner. The agency has yet to back a therapy that is widely available.

The agency expects to run out of cash for new awards by the end of next year. A $220 million private fundraising effort is being waged to help the agency along until November 2020. That's when CIRM backers hope that the agency's efforts will excite California voters enough for them to approve $5 billion more in funding via another citizen-based initiative.

Deeper involvement with industry is one way to produce quicker results. Venture capital firms are willing to move fast and bet big on research that they deem likely to produce handsome profits.

BlueRock focuses on cell therapies that target severe brain and heart conditions.  According to Biospace, the company expects its most advanced lead therapeutic, a compound for Parkinson’s disease, to begin clinical trials this year.

Vivo focuses on high quality companies in the United States and China but includes building companies from scratch. 

California also brings something to the game.  Karen Ring, the agency's Internet majordomo, noted last week on the agency's blog,

"CIRM is the world’s largest stem cell research funding institution dedicated to helping patients by accelerating the development of quality stem cell treatments. We’re currently funding 244 active stem cell research programs including 39 ongoing clinical trials."

Neil Litman, the agency's director of business development, said CIRM has a "unique vantage point" because of its broad scope. He said the new program is "essentially a built-in concierge service for the stem cell space."