Solomon and Stem Cells: California's Stem Cell Agency Is Slicing and Dicing Cash and Research Decisions

California's stem cell agency gave away $14 million this month, which could be described as less than a drop in its $3 billion bucket.

But the talk at the agency's awards meeting July 19 was not about largess. Instead it was about the lack of cash, lack of time and the need to split "babies" and "buckets."

"We are going to have to make some hard choices today," said one member of the agency's governing  board, Jeff Sheehy, a patient advocate member of the board for HIV.

"We are coming to the end," said another, Oswald Steward, director of the Reeve, Irvine Research Center at UC Irvine.

Sheehy and Oswald and others referred to the shrinking finances of the California Institute for Regenerative Medicine (CIRM), as the Oakland-based agency is formally known. It expects to run out of cash for new awards by the end of next year. Its leaders are trying to raise more than $200 million privately to tide it over until November 2020. That's when they hope another ballot initiative/bond measure will be approved by California voters and pump an additional $5 billion into the 13-year-old enterprise.

That was the backdrop at the session earlier this month. It was a meeting that illuminated the changing criteria that the agency is beginning to use  -- as the cash squeeze tightens -- to make decisions on who and what to finance. No longer will patient advocates or researchers be able to assume that an excellent scientific score assures that an application will be ultimately approved. Instead, "programmatic" considerations will play an important and perhaps definitive role.

Those considerations range from whether a researcher has received past funding from the agency, whether the application fits well within the agency's mission, whether an application fills a void in the agency's portfolio and just how innovative the research is, plus much more.

The discussion about diminishing resources arose when directors were given the usual list of applications that were approved for funding by its reviewers, who met earlier behind closed doors.  Normally, the reviewer decisions are rubber-stamped. This time, however, the 14 reviewer-approved applications totaled $19 million, but only $10 million was budgeted. That's when some directors brought up the need for Solomon-like decisions that would "split" the babies and the "buckets" of cash.

One upshot was that two applicants, James Hagood of UC San Diego and  Vittorio Sebastiano of Stanford, received only partial funding with the expectation that the board would approve a revision in the budget in late October. Nonetheless, those researchers were better off than six applicants who were also approved for funding by reviewers, but not by the CIRM directors. Final action on their applications was put off, probably also until late October.

The $10 million round involved basic types of research, but with a two-year time table. Directors also took action in another, separate round involving preclinical work. It dealt with only one application for $3.99 million, which was approved with no discussion. It went to Poseida Therapeutics, Inc., of San Diego for research aimed at supercharging  "a patient’s own immune system cells to attack and kill a treatment-resistant form of prostate cancer," according to the CIRM news release on all the awards. Poseida matched the award with $998,023.

It was the second CIRM award for Poseida, bringing its total from the agency to $23.8 million.  Here is a link to the summary of comments from reviewers on the Poseida application.

Below is a list of the other approved awards, all of which went to institutions that have links to a CIRM governing board member. Those members were not allowed to vote on those applications. Here is a link to a document which contains summaries of the reviewer comments on each application as well as ones that were not funded on July 

Application number	Title	Institution	Amount	Principal Investigator
DISC2-11131	Genetically Modified Hematopoietic Stem Cells for the Treatment of Danon Disease	UC San Diego	$1,393,200	Eric Adler
DISC2-11157	Preclinical Development of An HSC-Engineered Off- The-Shelf iNKT Cell Therapy for Cancer	UCLA	$1,404,000	Lili Yang
DISC2-11036	Non-viral reprogramming of the endogenous TCRα locus to direct stem memory T cells against shared neoantigens in malignant gliomas	UC San Francisco	$900,000	Hideho Okada
DISC2-11175	Therapeutic immune tolerant human islet-like organoids (HILOs) for Type 1 Diabetes	Salk Institute	$1,637,209	Ronald Evans
DISC2-11107	Chimeric Antigen Receptor-Engineered Stem/Memory T Cells for the Treatment of Recurrent Ovarian Cancer	City of Hope	$1,381,104	Saul Priceman
DISC2-11165	Develop iPSC-derived microglia to treat progranulin- deficient Frontotemporal Dementia	Gladstone Institutes	$1,553,923	Li Gan
DISC2-11192	Mesenchymal stem cell extracellular vesicles as therapy for pulmonary fibrosis	U.C. San Diego	$865,282	James Hagood
DISC2-11109	Regenerative Thymic Tissues as Curative Cell Therapy for Patients with 22q11 Deletion Syndrome	Stanford University	$865,282	Vittorio Sebastiano

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California Stem Cell Agency's Latest Online Event to Highlight ALS and Challenges to Research

California's $3 billion stem cell agency will mount its second Facebook Live event next Tuesday, featuring ALS researchers from Cedars-Sinai discussing their work and the challenges confronting the field.

The noon PDT cybercast will feature Clive Svendsen, director of the Regenerative Medicine Institute at Cedars, Robert Baloh, director of neuromuscular medicine at Cedars, and Ralph Kern, chief medical officer of Brainstorm Therapeutics, Inc., of New York City.

Viewers will be able to pose questions to the participants during the event, which has been dubbed "Ask the Experts.".

The stem cell agency, known formally as the California Institute for Regenerative Medicine (CIRM), has awarded Brainstorm $15.9  million to support a phase three clinical trial work in California dealing with ALS. Svendsen has received $24.9 million from CIRM, including $6.2 million for a phase one/two trial also involving ALS.  Baloh has received a $3 million CIRM award for research involving peripheral nerve disease.

CIRM's first Facebook Live event has drawn nearly 7.500 viewers since it was staged two months ago, a performance that makes it a useful tool in reaching large numbers of people.

Media Series on California Stem Cell Agency Has New Publication Dates

The San Francisco Chronicle has changed the publication dates for its series on stem cells and the California stem cell agency.

The second installment, dubbed "clinics,"  was scheduled to appear today. However, the publication date is now set for Aug. 2, one week from tomorrow. The rest of the schedule calls for the "research" installment on Aug. 16 and "progress" on Aug. 30.

Here is a link to an item on the beginning of the series earlier this month.

California Parkinson's Group Strikes Out on Path to Stem Cell Therapy; Clinical Trial, For-profit Company Goals

A San Diego patient advocate group for Parkinson's Disease is making a major financial move as it heads toward creation of a for-profit company to develop a stem cell therapy for an affliction that affects about one million people in the United States.

The group is the Summit for Stem Cell Foundation, which has been deeply involved in seeking funds from the $3 billion California stem cell agency. The Summit organization supports research being conducted by Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute.

Summit says it has raised $5 million as of this spring from a variety of sources. It estimates it will need $8 to $10 million to reach the stage where the federal government approves the beginning of a clinical trial. It also expects to raise more cash by avoiding the high administrative charges involving many research organizations.

Reporter Bradley Fikes of the San Diego Union Tribune wrote yesterday about the latest developments. He said Summit is moving out of its space at Scripps as it prepares to apply for funds for clinical research. Fikes wrote,

"The group has leased about 5,000 square feet, doubling its space, and as a parting gift Scripps Research is donating equipment from its stem cell center, saving the foundation nearly $1 million in start-up costs. At the same time, its overhead is dramatically reduced, said Jeanne Loring, the group’s lead scientist and professor at Scripps Research. (Loring is serving as the unpaid director of research for Summit.)

"A $2.4 million grant the group received from California’s stem cell agency ran out earlier this year, Loring said. Now the group can step up fundraising and add staff. It’s also soliciting more donated equipment."

Fikes continued,

"The group also plans to establish a for-profit company to get funding from investors interested in generating returns, Loring said. By drawing investments as well as philanthropy, the project gains access to capital not otherwise available.

"The group was inspired by the example of the Cystic Fibrosis Foundation, Loring said. In 2000, the foundation gave San Diego’s Aurora Biosciences $40 million to develop a cystic fibrosis drug."

Fikes reported that separation from Scripps has financial advantages dealing with what called "indirect costs." 

"Raising (donations) has been difficult, in large part because of the overhead issue, Loring said.

"Scripps Research imposes overhead of up to 94 percent, meaning that every dollar donated to the group required an additional 94 cents for the institute, Loring said. At the new location close by on Torrey Pines Mesa, overhead is roughly 10 percent.

"Lower overhead means the group can now apply for philanthropic grants that previously weren’t practical, she said, because donors prefer as much as their money as possible go directly to the cause."

Here is a video of Loring describing her work. 

A Good Sign for California's Stem Cell Agency? Californians Like to Say Yes to More Bonds

An ambitious campaign to stave off the death of the California stem cell agency with a $5 billion jolt of state borrowing could have an easy ride in a couple of years. 

At least that would seem to be the case if one bets on the odds as perceived in a column carried today in the Los Angeles Times. 

The headline on the piece by John Myers, the Times' Capitol Bureau chief in Sacramento, said,

"California voters almost always say yes to bonds..."

Myers wrote, 

"It’s the closest thing to a sure bet that exists in statewide campaigns, with an approval rate hovering around 90%."

Myers, however, focused mainly on this November's ballot -- not 2020. And he did not comment directly on the plan to present a $5 billion bond measure to voters in November 2020 to keep the stem cell agency alive.

The agency, formally known as the California Institute for Regenerative Medicine (CIRM), expects to run out of cash for new awards by the end of next year. Its only significant source of funding is money that the state borrows (bonds), which roughly double the costs of its operations because of interest expense. The borrowing was approved by 59 percent of the voters in 2004.

Myers related the current condition of the Golden State's indebtedness:

"State general obligation bond measures approved since 1986 total more than $167.7 billion. Lenders must be repaid with interest, averaging about 5% a year, over a span of several decades. Most general obligation bond payments come from the same bank account that provides cash for services such as education, healthcare and prisons." 

He continued, 

"A recent report by the nonpartisan Legislative Analyst’s Office estimated that California’s general fund is currently paying off $83 billion in bond obligations. Annual debt payments total about $6 billion. That’s roughly equal to a year and a half in general fund spending on the University of California system, or about triple what the state spends on firefighting."

"'When we make these decisions, we have to look at the big-picture context,' state Sen. Bob Hertzberg (D-Van Nuys) said during a legislative hearing last month on November’s slate of bond measures."

State Sen. Bob Hertzberg, News Growl photo

Hertzberg zeroed in on backers of a clean water measure on the fall ballot. The Times piece reported,

"'You’ve got to tell the truth,' he said to the measure’s proponents. 'You back up an armored car to the treasury, and you can take $430 million out of the back door because you can poll [on] something, spend a few million dollars because it’s an issue that looks sexy to voters, and draw the dough.'"

Myers continued,

"Voters are rarely asked to think about which needs government should meet. In 2004, they agreed to borrow $3 billion for stem cell research. In 2008, voters said yes to $9.9 billion in seed money for high-speed rail. Even though the (rail) bonds have only recently begun being sold to Wall Street investors, it’s debatable whether voters would make the same choice if asked again.

"And campaigns rarely offer enough information to fully consider the pros and cons of a bond measure. Voters must do their own homework, beginning with the understanding that a bond is a mandatory expense, an investment decision that can have profound impacts for more than a generation."

Expansive Media Series on California's Stem Cell Agency as It Nears Cash Cutoff

Lead photo on Chronicle stem cell series, photo by Gary Wathen

The San Francisco Chronicle today kicked off a major look at California's $3 billion stem cell agency with a multimedia presentation that covered everything from stem cells and how they work to the desperation and hope of patients with all-but-untreatable afflictions..

The four-part series will roll out over the next six weeks in the Chronicle, which says it reaches 1.7 million persons weekly in the San Francisco Bay Area via both print and electronic means. The series looks to be the most expansive look ever at the agency, which is formally known as the California Institute for Regenerative Medicine (CIRM).

The Chronicle effort, which has been many months in the making, comes as the agency is facing its lingering demise unless efforts to raise more billions are successful. CIRM expects to run out of cash for new awards by the end of next year. It is attempting to raise privately more than $200 million to bridge a financial gap with the hope that voters will approve a yet-to-be-written, $5 billion bond measure in November 2020.

The series is likely to have a significant foundational role in more news coverage of the agency as it nears its cash cutoff. As a starting point, reporters will be examining the Chronicle's work and other previous coverage of CIRM, which has all but vanished from news pages and news screens of California readers.

Patient Hopes and Unregulated Treatments

The initial installment in the Chronicle series, written by Erin Allday, had little specific to say about the agency, but dwelt on patients' hopes of finding unregulated stem cell therapies both within California and outside of the state. One piece served as a primer and was called "What Are Stem Cells and How Do They Work." The other two major pieces were headlined,

"In Search of a Miracle: She Tried Everything to Heal Her Son; Stem Cells Were Her Last Hope"

and

"Driven by Desperation: Out of Options, Six Patients Turn to Stem Cells."

An editor's note tied to the series said,

"'The Miracle Cell' explores the hope and reality of the revolutionary science of stem cell therapy. It focuses on what has transpired since 2004, when California voters approved a $3 billion bond measure to fund stem cell research with the promise that it soon would produce new treatments for incurable diseases.

"In four parts, it follows the stories of patients desperately seeking remedies; probes the for-profit clinics where unproven and unregulated treatments are being offered; takes you into the labs and hospital rooms where scientists are testing new therapies; and provides a comprehensive accounting of what California’s multibillion-dollar bet on stem cells has achieved."

The main piece today dealt with a nine-year-old boy from Scott's Valley, Ca., who received stem cell treatments in Tijuana. The story also documented the "powerful allure" of the therapies. Allday wrote,

"In 2004, California voters were so convinced that cures from stem cells were close at hand that they approved Proposition 71, a $3 billion bond measure to pay for research that the federal government would not.

"Nearly 15 years later, no proven therapy has emerged. But some doctors already claim to have tapped stem cells’ potential. And some patients refuse to wait any longer to seek treatment."

Asterias and Paralysis 

One of the six profiles of patients involved Mary Ambery, 59, who was paralyzed from the neck down in a fall in 2017. She is now engaged in a clinical trial run by Asterias Biotherapeutics, Inc., of Fremont, Ca.  The Chronicle reported, 

"Before the transplant, she had almost no movement in the muscles that allow her to bend her arms at the elbows and rotate her wrists. She couldn’t pinch her thumb and forefinger together. She couldn’t feed herself or comb her hair, couldn’t use a smartphone or a pen.

"More than a year after the surgery, she can do her own makeup and hair. She can use a fork, but needs help cutting up her food. She can text with her friends, she can write 'pretty legibly.'"

The story did not mention that Asterias' work has been supported by $21 million from the California stem cell agency.  

The next installments in the series are likely to contain more details on the Golden State's stem cell program. Here are the one-word topics and expected dates of publication: Clinics, July 25; Research, Aug. 8, and Progress, Aug. 22.

Stanford's Weissman Lauds California Stem Cell Agency For Innovation, Critical Financing

The California stem cell agency has chalked up hearty praise from an internationally known Stanford researcher for its 13-year, $3-billion search for stem cell therapies and cures.

Irv Weissman, Stanford photo

The scientist is Irv Weissman, director of the Institute of Stem Cell Biology and Regenerative Medicine at the Stanford University School of Medicine.  His laudatory reflections on the California Institute for Regenerative Medicine (CIRM), as the stem cell agency formally known, recently found their way to the Oakland-based enterprise. And last Monday the agency posted an item on Weissman's remarks on its blog, The Stem Cellar.  The article began,

"When you get praise from someone who has been elected to the National Academy of Sciences and has been named California Scientist of the Year you know you must be doing something right."

Weissman said the agency has provided the financial support that allows research to bypass "the valley of death," short hand for the stage in which promising research can often die. Plus, he said, CIRM allows the discoverers to guide early stage development rather than diverting it into commercial arena.

Weissman's comments spoke to what the agency calls its "value proposition," a term that is becoming increasingly important as the agency faces its possible demise. The agency expects to run out of cash for new awards by the end of next year. It is trying to raise more than $200 million privately to continue operations until November 2020, when it hopes voters will approve $5 billion more for stem cell research.

CIRM's blog item was authored by Kevin McCormack, CIRM's senior director of communications,  in the context of a $115 million initial public stock offering by Forty Seven, Inc., of Menlo Park, Ca., a company founded on the basis of Weissman's work. Weissman is currently a member of the company's board.

Forty Seven has received $15.2 million from CIRM. Weissman has received $32.4 million.

Weissman said in the statement that CIRM carried,

"The major support (for Forty Seven) came from the California Institute of Regenerative Medicine (CIRM), funded by Proposition 71, as well as the Ludwig Cancer Research Foundation at the Ludwig Center for Cancer Stem Cell Research at Stanford. CIRM will share in downstream royalties coming to Stanford as part of the agreement for funding this development.

"This part of the state initiative, Proposition 71, is highly innovative and allows the discoverers of a field to guide its early phases rather than licensing it to a biotech or a pharmaceutical company before the value and safety of the discovery are sufficiently mature to be known. Most therapies at early-stage biotechs are lost in what is called the ‘valley of death’, wherein funding is very difficult to raise; many times the failure can be attributed to losing the expertise of the discoverers of the field.”

In response to a question from the California Stem Cell Report, McCormack said Weissman's statement came "unbidden" by the agency.  We asked Weissman about what led him to issue the remarks. Weissman said he said he had not seen the CIRM piece, but responded after reading it.

He said in an email, 

"Now that I’ve seen the quote, it is close to what I sent to colleagues at Stanford. I did it so that my colleagues understood the nature of the CIRM experiment in funding research and its translation. One of these colleagues sent it on to CIRM, and I didn’t object.

"I think its very important to know how the original Prop 71 was designed not only to fund stem cell related research, but also to take selected projects competitively reviewed by expert referees to and through phase 1 trials if warranted. The therapy that was developed at Stanford by the team led to the discovery team forming a disease team of experts usually only found in biotechs and pharma, but here led by the discoverers of the leukemia stem cell overexpressed molecule, CD47, which by its ‘don’t eat me’ actions protects the leukemia from removal by scavenger macrophages. The CIRM oversight team helped guide selection of outside advisors, and met frequently with us to monitor our progress, and most importantly, give us advice that led to Stanford filing two INDs on time in the US [FDA] and the UK[MHRA]. The importance of doing high level preclinical testing and toxicity etc without a profit motive allowed the team to keep going when surprising events came up. Many biotechs fail at that point, as the risk starts to worry investors and shareholders. But this went through, and in addition to getting into important phase 1 trials that broadened the potential cancer targets to cancers beyond myelogenous leukemia, the group could see how the therapy needs to be administered to avoid toxicity in patients. By the time Stanford informed us it was time for them to license the ip, many independent companies had formed around the concept discovered by the team, a validation that this could become the second type of checkpoint inhibitor therapy for human cancers, this time for macrophages instead of inhibited T cells. 

"I felt it was equally important to try to get the agency that funded these stem cell related efforts to share royalties with the academic institution that held and licenses the intellectual property; I first raised this issue in 1994 when I was President of the American Association of Immunologists; my article is attached here.

"Most of us hope the discoveries we make can have the potential to help patients with diseases that are only incompletely treated by current medical practice. Very early results of clinical trials reported in the ASCO meeting in early June are consistent with that possibility. 

"I need to make clear that the statement in the blog was written by me, and was not an official document of Stanford University, of Forty Seven, Inc, or from others from the discovery team. If you decide to publish this answer to your question, please either publish it in full, unedited, or don’t publish it at all. I didn’t write this for you to publish, but for you to understand from your question the reason I wrote the original document to colleagues at Stanford."

Now Official: California Stem Cell Scientist Loses Congressional Race

For those of you who may have missed the news, Hans Keirstead, the former UC Irvine stem cell researcher, has officially lost his bid to become the first stem cell scientist elected to Congress.

He had a close finish in a primary race that went to Harley Rouda, a former Republican, who will be attempting to oust Republican Rep. Dana Rohrabacher this fall. The final vote count showed Keirstead with 125 votes less than Rouda. Both Rouda and Keirstead are Democrats.

Keirstead was a proponent backer of the ballot initiative that created the $3 billion California stem cell agency.

Here are links to stories about the race, which delved into Keirstead's time at UC Irvine, and the results: Voice of OC, Mother Jones.

California Backs Research for Brain Cancer and Parkinson's with $9.5 Million

OAKLAND, Ca. -- The California stem cell agency today awarded $9.5 million for two late stage preclinical projects for development of therapies aimed at brain cancer and Parkinson's Disease.

A $5.8 million award for Parkinson's went to Krystof Bankiewicz of UC San Francisco and Clive Svendsen of Cedars-Sinai. A $3.7 million award for glioblastoma, a form of brain cancer, went to John Zaia of the City Of  Hope. Glioblastoma is the form of cancer that has afflicted U.S. Sen. John McCain.

In a news release from the agency, known formally as the California Institute for Regenerative Medicine (CIRM), its CEO, Maria Millan, said,

“Glioblastoma is the most common, and the most aggressive, form of brain cancer that led to the death of U.S. Senator Ted Kennedy and former Vice President Joe Biden’s son Beau Biden. 

"CIRM has supported a variety of stem cell-based approaches to target this devastating and currently untreatable condition.  The project approved by our board today is unique in that it seeks to use gene modified stem cells to allow patients to tolerate the high doses of chemotherapy while also making these tumors more susceptible to the chemotherapy.”

Regarding the Parkinson's award, the agency has already pumped $22.3 million into a phase one clinical trial being conducted by Svendsen for treatment of ALS with the same neural progenitor cell product that will be used in the Parkinson's research.

Here are links to the review summaries on the Parkinson's application and the glioblastoma application, plus additional information.

Application Number	Principal Investigator	Institution	Target	Amount Awarded	Public Summary of Review
CLIN1-10967	John Zaia	City of Hope	Glioblastoma	3,684,259	Ex Vivo Gene Engineering of Blood Stem Cells for Enhanced Chemotherapy Efficacy in Glioblastoma Patients
CLIN1-11059	Krystof Bankiewicz/ Clive Svendsen	UC San Francisco/ Cedars- Sinai	Parkinson’s Disease	5,811,340	MRI Guided Delivery of Neural Progenitor Cells Secreting GDNF for the Treatment of Parkinson's disease

California Stem Cell Agency Eyes Changes in Funding Decisions; Possible Impact on Bond Election, Development of Different Therapies

A CIRM slide outlining current programmatic criteria. GWG
refers to the group that reviews applications.  The
 subcommittee reference is to the panel of directors  who
ratify reviewers' decisions. ICOC is the abbreviation for
the name of the governing board.

The $3 billion California stem cell agency is re-examining its criteria for awarding hundreds of millions of dollars with an eye to placing more emphasis on what could be called non-scientific criteria.

The move could have an impact on hundreds of researchers in the state and the development of stem cell therapies that could benefit untold numbers of patients afflicted with a host of deadly and debilitating diseases. It could also have an impact on a possible ballot measure to provide an additional $5 billion for the 13-year-old stem cell program.

The changes could be acted on as early as tomorrow at a meeting of the governing board of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. The meeting is in Oakland, but Internet access is available for those who wish to comment and hear the proceedings.

The move comes under the rubric of "programmatic review" of applications for funding. It has been an ill-defined term for years at the agency. But more specificity was disclosed yesterday in a series of 20 slides scheduled to be shown at tomorrow's meeting of the agency's 29 directors. The posting of the slides came less than two days prior to the meeting.

The agency's staff has laid out seven possible areas where changes might be made:

• "Annual Program Budget and Goals
• "Value Proposition of Proposed Project
• "Patient population, competitive landscape
• "Relevance of Project to Stem Cells
• "Contribution to CIRM Portfolio
• "Disease area, current award overlap
• "Previous CIRM Support of Project"

The full impact of increased use of any or all of those criteria was not clear from the slides provided by the agency. But it could mean that an application that received a high scientific score could be sidelined in favor of one that fills a void or bolsters a weak spot in the CIRM award portfolio.

CIRM slide on possible new award criteria 

Over the years, many CIRM board members have expressed frustration with how the scoring on some applications works. In the case of some applications, only one point separates those receive millions and those who receive none. The concern has been that a one point difference is less than meaningful.

The slides do not flesh out all the likely reasons for putting more emphasis on non-scientific issues, but the agency is approaching the end of its life. It expects to run out of cash for new awards at the end of next year.

A private fundraising effort is underway to tide the agency over until, it is hoped, voters approve $5 billion more for the agency in November 2020.

Changes in award criteria could lead to approval of research whose results are more likely to resonate with voters in time for a ballot measure campaign in two years.

CIRM was created in 2004 by voters who were swayed by a campaign that raised expectations that stem cell cures were just around the corner. The agency has yet to produce a therapy that is available for widespread use. However, it has helped to fund 49 clinical trials, which are the last stages before a therapy is approved by the federal government for general use.

California Stem Cell Agency Steps Up Public Access to Key Meeting This Week; Brain Cancer and Parkinson's On Tap

Stem cell researchers and the public -- from wherever they are around the world -- will have a chance Thursday to take part remotely for the first time during a meeting of the governing board of California's $3 billion stem cell agency.

The session will include approval of two awards totaling $9.5 million, approval of a $16.8 million operating budget, approval of a revised conflict of interest code along with a quasi-mysterious matter dealing with "programmatic tools."

At the time of this posting, the agency, formally known as the California Institute of Regenerative Medicine (CIRM), had not added online any background material supporting the cryptic, agenda item. However, the general subject deals with decisions that the board makes on applications for funding. In addition to scientific considerations, the board can base its decisions on non-scientific matters, such as whether the application really fits with the CIRM program.

(After this item was posted, the agency added to the agenda a number of slides dealing with the grant-making process and use of programmatic criteria. The California Stem Cell Report will carry an item on those slides tomorrow. Update: That item has now been posted.)

Interested persons will be able -- for the first time -- to make comments not only that matter but others from wherever they are. But they must be logged on to the audiocast/webcast of the session in order to be recognized. The agenda contains directions on how to do that. During the meeting, online participants will be asked if they have a comment. We recommend setting up the connection in advance of the meeting. It may require some tweaking, depending on your computer figuration.

The agency has successfully tested the new public comment feature on a few committee hearings. This will be the first experience with a full board meeting.

The awards expected to be made include a  $5.8 million application for Parkinson's disease and a $3.7 million application for glioblastoma, a form of brain cancer. Reviewers, meeting behind closed doors, have already approved the awards. The board must ratify their decisions in public. (Here are links to review summaries on the Parkinson's application and the glioblastoma application, plus comments by a Scripps Research Institute scientist on the Parkinson's application.

John Zaia of the City of Hope wrote a letter to the board commenting on the public summary of his glioblastoma application, critiquing reviewer comments. He said,

"Based on our experience with two previous FDA-approved pilot trials, we foresee no major hurdles to completing an IND, recruiting patients, manufacturing the therapeutic cell product, and eventually conducting the clinical trial."

The agency does not release the names of applicants until action is taken by the board, but when a letter is written by an applicant, his/her name becomes public along with the letter.

The proposed budget for the 2018-19 year stands at $16.8 million, up 7 percent from an estimated spending of $15.7 million for this fiscal year. The budget for research awards is separate and has been normally set in December. However, some board members have indicated that are are interested in trimming the amount of awards to be given annually in order to extend the life of the agency.

Under current spending rates, the agency expects to run out of money for new awards by the end of next year. It is pinning its hope for survival on a private fundraising effort now underway and voter approval of a proposed $5 billion bond measure in November 2020.  An update on the fundraising effort may be presented Thursday by CIRM board chairman J.T. Thomas.  

California's "Huge Ecosystem" for Stem Cells: The View from Europe

Some folks in Europe are worried about stem cell research, particularly about organizations like California's $3 billion stem cell agency.

The alarm was sounded just yesterday in Horizon, which calls itself  "The EU Research and Innovation Magazine."

The article in question (the second most popular on its web site at midday today) was headlined:

"Europe is in danger of being out-innovated in regenerative medicine"

Ton Rabelink, Arno Massee Fotografie

The piece consisted of an interview with Ton Rabelink, professor of internal medicine and head of Leiden University in the Netherlands. He cited the California agency as a "huge ecosystem" for developing much needed stem cell therapies.
nephrology at

Rabelink said that the European Medicines Agency is wrestling with finding the "the right mechanisms to support the field."

‘It is very important that they do this because the regulatory landscape in the US and Japan has changed over the past two or three years to accommodate recent advances. For example, Japan has an early access programme for treatments that seem promising but are not yet proven to work. If they appear safe in say, 40 patients, then doctors can start applying them. The US has created the 21st Century Cures Act that allows for clinical trials for stem cell therapies and fast-track access to market for those that appear effective."

Rabelink said,

"The risk is that if we don’t organise locally here in Europe, we’ll end up having to buy these treatments from those countries. We’ve already seen this with genetically modified cells, so-called CAR cells, to attack tumours in leukaemia. The treatment works quite well but costs about €500,000 ($582,670) per patient.

"It's very interesting to look at what happens in the rest of the world. You really need ecosystems — academia, but also legislatures, manufacturing and, of course, finance. The US has huge ecosystems like CIRM, the California Institute for Regenerative Medicine, which was founded through taxpayers’ money following a referendum, and invests about $250 million per year in this space. (The agency actually was created by a ballot initiative, which is much different than a referendum.)

The Dutch researcher continued,

"The situation in Japan is even more remarkable. The early breakthroughs were made by a Japanese scientist so they consider regenerative medicine almost as their national invention. And, of course, Japan has an ageing population so the concept is very appealing. The government set up a planned economy around regenerative medicine and adapted its regulatory framework, putting national systems in place to oversee quality and safety and organising private-public collaborations, bringing together academic institutions and big pharma. Fujifilm, which was originally a photographic company, is devoting resources to stem cell research and using its film technology to make biomembranes.’

New California Stem Cell Agency Board Member: Suzanne Sandmeyer of UC Irvine

A woman who is a medical doctor as well as a professor of both chemical engineering and microbiology and molecular genetics is joining the governing board of the $3 billion California stem cell agency.

She is Suzanne Sandmeyer, vice dean of research in the School of Medicine at UC Irvine. Her appointment by the UC Irvine chancellor was announced today by the California Institute for Regenerative Medicine (CIRM). 

UC Irvine has long held positions on the 29-member governing board of the agency, which was created by California voters in 2004. UC Irvine and its researchers have received $114.3 million from CIRM, ranking sixth among all recipients. Roughly 90 percent of CIRM awards has gone to institutions with ties to members of its board.

In its news release today, the agency quoted Sandmeyer as saying,

“Our country has one of the most expensive systems of medical care, and yet we don’t have the longest-lived population. I want to work toward reducing the burden of medical expenses for people. I am very excited about the potential of stem cells to treat many disorders and the potential for new technologies like CRISPR to further empower that approach.”

The agency's news release also noted Sandmeyer's broad range of interests outside academia.  She was quoted in a CIRM blog item as saying:

"I go through phases like everyone. There is never enough time. My favorites are astronomy, bird photography, guitar, biking, kayaking, reading and of course German shepherd dogs."

She replaces Howard Federoff also of UC Irvine, who is stepping down to devote more time to his research, CIRM said.

Stem Cell 'Ethical Tensions,' Recouping the Public Investment, Affordability and Much More

"Staggering" amounts of public money have been spent on stem cell research, and "care must be taken" to assure that commercialization does not exact an excessive "human or monetary price," according to an article this week in the journal Science.

The cautionary note was sounded in the prestigious publication while the world's largest stem cell gathering is underway in Australia with more than 2,500 researchers and others in attendance. Plus next week, the $3 billion California stem cell agency convenes its directors to mull over its own programs and give away more millions. 

Written by Douglas Sipp, a researcher at RIKEN in Japan, Megan Munsie of University of Melbourne and Jeremy Sugarman of John Hopkins University, the Science article said

"Ethical tensions related to stem cell clinical translation and regulatory policy are now center stage...."

They said that expedited government procedures for use of stem cell treatments have been set up in the United States, Japan and Italy. At the same time, they wrote, 

"A staggering amount of public money has been spent on stem cell research globally."

The article declared, 

"The state and the taxpaying public's interests should arguably be reflected in the pricing of stem cell products that were developed through publicly funded research and the regulatory subsidies. Detailed programs for recouping taxpayers' investments in stem cell research and development must be established."

They warned, 

"Care must be taken to ensure that entry of stem cell–based products into the medical marketplace does not come at too high a human or monetary price."

Another journal article this week also sounded cautionary notes. Written by Paul Knoepfler of UC Davis, it was titled: 

"Too Much Carrot and Not Enough Stick in New Stem Cell Oversight Trends"

Knoepfler addressed the Food and Drug Administration's efforts to speed use of stem cell therapies. He wrote in Cell Stem Cell and also on his blog, saying,

"It’s been remarkable to see the FDA approve up to 20 regenerative medicine advanced therapy(RMAT) designations in just over a year. However, I think there’s a strong possibility the agency has swung too far from the too slow review of stem cell and regenerative medicine investigational therapies in the past to now going at warp speed. Since none of the current 20 designated RMAT products had any kind of prior expedited review designation given, is it reasonable to think all 20 now meet rigorous enough standards and all because of new data? It’s hard to say, but there’s likely a spectrum of existing data behind these RMAT designated studies.

"We won’t have an overall RMAT verdict for years as the RMAT trials play out. However, I predict that the agency has lowered the bar too far. There are also concerns that the conditional approval system in Japan is too liberal, as evidenced by discussion over the approval of a recent IPS cell cardiovascular study. Taken together this is what I mean by 'too much carrot.'  Another issue with RMAT is that the criteria by which the designations are given (or not) are not clear." 

Next Thursday, the governing board of California's $3 billion stem cell agency is scheduled to meet to give away more millions for stem cell research in the Golden State. The agency will also be examining the non-scientific considerations that it uses in deciding which applications to fund. It may be that some of the issues raised by these four researchers will also come into play.

Safety and Effectiveness Concerns Raised about $5.8 Million California Stem Cell Research Proposal for Parkinson's

A California stem cell scientist yesterday commented on an application before the state's stem cell agency for $5.8 million for research into a possible therapy for Parkinson's disease, which afflicts as many as 10 million persons worldwide.

Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute, made the remarks concerning a proposal that is likely to be approved June 28 by the governing board of the $3 billion agency.

Her comments came in an email to the California Stem Cell Report after it asked for her thoughts on the review summary of the application (CLIN1-11059), which has been already approved behind closed doors by the agency's scientific reviewers. The vote was 9-6-0 with nine reviewers voting to approve it and six reviewers saying it needed improvement and should be resubmitted. No reviewers voted outright against it. The summary of the review and application can be found here. 

The name of applicant is not known. The stem cell agency withholds the identity of applicants until an application is ratified by the full board in a public session.

As Loring notes in her email, she is also conducting research on Parkinson's and also has funding from the stem cell agency, formally known as the California Institute for Regenerative Medicine. Here is the text of her email along with links to the two research papers that she cites.

“Researchers have explored many approaches to treatment of Parkinson’s disease over the last several decades. The tremors and freezing in PD are caused by the progressive loss a specific type of dopamine-producing neuron in a part of the brain called the substantia nigra. Half of these neurons have died by the time the disease is diagnosed.

“The only approach that has resulted in long-term reversal of the symptoms of PD is transplantation of human fetal tissue containing the precursors of that specific type of dopamine neuron. 

“The therapy that we are developing is based on the success of those fetal studies; our particular approach is to use patient-specific dopamine neurons produced from their own induced pluripotent stem cells (iPSCs). The arguments in support of this therapy have been published (see below).

“We share this idea for neural replacement therapy with several other groups worldwide: Roger Barker in the UK, Malin Parmar in Sweden, Jun Takahashi in Japan, and Lorenz Studer in New York are using human embryonic stem cell-derived neurons or unmatched iPSCs. We are the only group among these that is using matched neurons so there will be no need for immunosuppression.

“These are my concerns about any therapy using undifferentiated neural stem cells and gene therapy:

“Safety concerns:

“Neural stem cells are dividing cells that have been known to make tumors; one patient in California had a tumor grow in his spine after receiving neural stem cells from a clinic that did not have FDA approval, to treat a stroke. A few years ago there was a proposed treatment for Alzheimer disease that used neural stem cells, and in that case there was clear evidence that those cells made tumors in animals; it was funded by CIRM. Our cells are not dividing, and we have done a one-year study in rats to make sure no tumors form.

“Addition of a transgene for a neural growth factor, GDNF, to the cells, will require thorough testing because transgenes can disrupt the genome, and the expansion of the cells increases the risk of other mutations arising, such as the p53 mutations that we discovered in hESCs a few years ago. p53 is a very bad actor; mutations in this gene are found in half of all cancers. The applicants should be planning to sequence the genome of the cells to be improve the chances that the cells are safe; we sequence our cells.

“Effectiveness concerns:

“Survival vs. replacement.

“There are two general approaches to cell-based treatment of Parkinson’s disease. The neural stem cell approach is not intended to REPLACE the dying neurons. It is intended to help the remaining dopamine neurons survive longer. The other approach, neuron replacement therapy, can reverse the symptoms long-term.

“Immunosuppression. It is necessary to suppress the immune system whenever a transplantation of unmatched cells or tissues is performed. Immunosuppression is a concern for neurologists who are treating PD patients, because it weakens the immune system and makes patients more susceptible to serious debilitating infections.

“The neural stem cells making GDNF may be a good solution for the debilitating neuronal loss in ALS, and CIRM is already funding their use for that disease. But please ask a few neurologists what they would advise their patients with Parkinson’s disease. Those I’ve asked would prefer replacement of dopamine neurons, rather than a treatment using transplantation of dividing cells pumping a nerve growth factor into the brain, that requires immunosuppression. Historically, this has not been a good idea.”

Here are two links to articles that Loring cited. See here and here.