The FDA and the Loss of Gottlieb: What Does it Mean for Stem Cell Research?

Scott Gottlieb at his earlier Senate confirmation hearing

"Panic Attack" --That's what the headline this morning said about the resignation of Scott Gottlieb as head of the Food and Drug Administration(FDA). 

The STAT article addressed the general biotech field and its worries. Gottlieb's departure, however, also creates some uncertainty involving California's $3 billion stem cell agency. Known as the California Institute for Regenerative Medicince (CIRM), the agency is backing 51 clinical trials, all of which are regulated by the FDA.

STAT is one of the more authoritative outlets dealing with medical research news. Its Gottlieb piece reviewed his impact on stem cell and regenerative medicine and what his loss might mean. The full headline said, 

"Scott Gottlieb's Sudden Resignation Will Give Biotech a Panic Attack"

The article by Matthew Herper and Adam Feuerstein said,

"Without Gottlieb at the helm, there is uncertainty. And there is nothing that scares investors and biopharma more."

Most of the news coverage of Gottlieb's surprise resignation focused on his efforts regarding vaping and opiods.  But STAT was not alone on discussing the stem cell/regenerative medicine issues. A piece on Politico said, 

"Gottlieb worked to advance cell and gene therapies, a promising new area of medicine. Under his leadership, the FDA put out a framework for regenerative medicines, designed to accelerate the approval of the most promising gene therapies. At the same time, Gottlieb balanced promoting legitimate new treatments with crackdowns on bad actors who were taking advantage of patients by marketing unapproved, unproven and potentially dangerous treatments."

In California, the state has invested roughly $2.5 billion so far in stem cell research with goal of bringing products to market. That is a process that heavily involves the FDA.

Indeed, a top official of the FDA will be speaking next month at a San Francisco conference sponsored by the agency and UC San Francisco. The topic? "Regulation and the Office of Cell Therapy and Gene Therapies Expedited Reviews"

It is far from clear what will emerge at the FDA concerning regenerative medicine or whether Gottlieb's approach will continue.  President Trump may leave the post vacant for some time. He will be heavily lobbied by interests that have opposed Gottlieb's more visible efforts concerning vaping and opiods. 

Trump also will feel pressure from the regenerative medicine industry. But given the multiplicity of issues facing the president, the FDA is not likely to be high on Trump's priority list. And then there are Senate confirmation hearings on any appointment.

Meanwhile we can expect to see more analysis in the coming weeks of what it all means for stem cells and regenerative medicine. 

A Chance to Peek Inside a $50 Million California Stem Cell Program

Video from 2017 Alpha Clinic symposium

One of the better stem cell, show-and-tell conferences is coming up this spring in San Francisco, plus it is free and open to the public.

The day-long session will provide a peek inside one of the signature efforts of California's 14-year-old, $3 billion stem cell research program, which is edging closer to ever more critical financial times. 

The meeting April 18 is the fourth annual Alpha Clinic symposium. The Alpha Clinic Network was created in 2015 by the California Institute for Regenerative Medicine(CIRM), as the stem cell agency is formally known. 

CIRM has pumped $50 million into the network, which is aimed at delivering clinical trials to patients, creating strategic relationships between science and industry and leveraging statewide resources. Sites for the network are located at the City of Hope and at UC campuses in San Francisco, Davis/Sacramento, San Diego, UCLA and UC Irvine.

For those interested in California public policy issues dealing with health, medical mattters and research, the symposium will offer an up-close opportunity to check out the impact of the state stem cell agency. 

The session promises updates on stem cell research and clinical trials on afflictions ranging from sickle cell disease to cancer along with a look at gene editing. Scientists and patient advocates will be telling their stories and detailing the research.

CIRM is scheduled to run out of cash for new awards this year. It is attempting to raise privately $220 million to bridge a financial gap before hoped-for voter approval of $5 billion more in funding in November 2020.

Geoff Lomax, CIRM's senior officer for strategic infrastructure, told the California Stem Cell Report via email last week:

"It’s an exciting time in medicine as we have the tools to literally mend cells at the DNA level. The annual symposium is an opportunity to hear from the pioneers who developed these tool, the Alpha Clinic doctors and nurses that use them and the patients that have benefited from them."

Here are links to more information about the Alpha Clinic Network: Agenda for the symposium. CIRM's Alpha Clinic page, a CIRM blog item on the April meeting. 

The session this spring is financed with $60,000 from the stem cell agency.

California Stem Cell Program Trying to Build $220 Million Financial Bridge: An Update

For many months now, California's stem cell research program, which expects to run out of cash by the end of this year, has been seeking to raise privately $220 million. But it has yet to report that it has snagged a significant chunk of that amount.

The most recent overview of the current fundraising effort came last December at a meeting of the governing board of the California Institute for Regenerative Medicine (CIRM), as the state stem cell agency is formally known. 

Jonathan Thomas
CIRM photo

Jonathan Thomas, chairman of the CIRM board, briefed the panel on the progress of the effort to create a financial bridge to the hoped-for passage of a possible $5 billion ballot measure in November 2020. 

The fund-raising effort is targeting high net-worth, potential donors and medically oriented foundations with a smorgasbord of philanthropic options. The choices can be tailored to a potential donor's appetite, including supporting specific types of research, Thomas said. 

Thomas is expected to update the board on the fundraising effort at its next meeting March 21, which will be based at its Oakland headquarters. The session will also be available on the Internet with remote hook-ups that will allow members of the public to comment and ask questions.

CIRM was created by voters in 2004 who also provided it with $3 billion in state bond funding. No additional source of cash was established.  At the beginning of this year, the agency was down to its last $144 million for new awards. It has set aside cash for administering its final awards should a new bond measure fail to pass. 

Here is the text of what Thomas told the 29-member board in December about the fund-raising drive. The text comes from the transcript of the meeting.

“So I'm going to move next to a report on the bridge fundraising, sort of a year-in-review summary. As you recall, through the end of last year (2017), we had secured 7 million from Bill Bowes and Pitch Johnson. We talked about that earlier (2015). (The funds are allocated for a "wind-down.")

“At our December board meeting last year, when we reported on the fact we were aware we're going to be out of funds potentially by the end of 2019, we talked about a couple things. One, Bob Klein (former chairman of the agency’s governing board) was here and talked about his potential intent to run a new bond measure in the november 2020 general election for $5 billion. 

We, also at that meeting, discussed the fact that we would like to be able to keep things going at a normal pace between the time we had run out of money, which we anticipated to be late 2019, and the election. And so we decided at that point that we would look to pursue bridge funding to fill that gap ideally in an amount equal to roughly the average of what we put out over the last few years.

“So the vision at that time was to raise bridge funds to not only go through 2020, but, if successful in 2020, the next actual realization of bond proceeds would be in the spring issuance by the state treasurer of bonds on behalf of all state agencies funded out of the state treasurer's office. So it would really be getting from late 2019 to spring of 2021.

“The idea was all of that money had to be raised in a staggered way through the last installment in the middle of 2020. A note that this is just referring to research funds. We have admin funds earmarked currently all the way through 2023.

“The strategy at that point to pursue the vision was to identify the most likely parties interested in medical research both in California and in the rest of the country. We spent a great deal of time doing that.
“Secondly, to tailor the asks to specific candidates that we felt would be the most successful in terms of what we were pitching. Thirdly, to approach those candidates either directly or through third-party intermediaries well known to the candidates. And the theory there is not only is how you ask is important, but who gets you in the door to ask is vital.

“So we've spent a lot of time analyzing who the correct third-party intermediary would be who would have individual and direct contact with the candidates in question. We've had weekly meetings of our fund-raising team, consisting of myself, Maria Millan (CIRM president and CEO), Maria Bonneville (vice president of administration for CIRM), Scott Tocher (CIRM general counsel), and Eliana Barnett (senior executive assistant in CIRM's office of president), to discuss strategy as we continue to update. And we have coordinated with Bob Klein's office and with Melissa King (executive director of Americans for Cures) of Bob Klein's office on these discussions. (Klein founded Americans for Cures.)

“The plan to implement the strategy is to offer a menu of fund-raising options including charitable gifts, the loan product that we discussed that tied to the election, program-related investments, and other derivatives of those ideas. We developed that menu of options in consultation with legal counsel, bond counsel for the state, the state treasurer's office, the state controller's office, and other outside parties with relevant input, such as those that have had programs that we might wish to emulate. Note that we're asking for a variety of things, including unrestricted gifts or loans or gifts or loans to specific projects or conditions or whatever.

“The idea with the gift would be, or loan, if you put money in, not only would it enable the bridge period, but it would allow for giving us the most credible shot of getting an election passed in 2020, at which time, whatever your particular interest would be, if the measure passed, you would have a tremendous leveraging effect. 

“So if you were to put in, for example, 50 million and the measure passed, you've have a hundred-to-one leverage that would result from that, a good chunk of which could go towards whatever your specific interest was.

“So as we've been developing those ideas, we've been refining the asks as we've gone along in terms of what feedback we get as to what sounds more appealing or less appealing.

“To date, implementing that plan, which is connected to the strategy, we've met or had confidential calls with dozens of stakeholders, including ultra high net worth individuals whether individually or in groups.

“I referenced an event that Bob and I did in the summer in the Palo Alto area for a number of family offices. We've also talked, met with major foundations, with corporations who have an interest in the medical research space, and with numerous third-party intermediaries of the kind I described earlier. The way it sort of is broken down, been looking at funding either CIRM generally or with respect to specific projects, which I've sort of taken the lead on. Maria Millan has done a lot of great work in developing project-specific related asks for different initiatives that CIRM either has or would consider having that would get the fundraisers in the game.

“To date, as you might expect, a number of the meetings that we've had, the people we have talked to have, as far as the pitches go, either declined respectfully, others are ongoing as we speak. Since the last board meeting, we've continued our strategy discussions of third-party intermediaries. We've had several approaches to specific ultra high net worth individuals either in person or through these intermediaries. As before, a number of those have declined. However, there are a number of those discussions which are ongoing.

“We've calendared a number of meetings with potential stakeholders between now and the next board meeting, including meetings with major foundations, ultra high net worth, again, either in person or through third-party intermediaries. In addition, we have two group meetings similar to the one we had in the summer with family offices scheduled for the first quarter, which are one in San Diego and one in Los Angeles.

“So that is sort of where we are at this point. We continue to look for our anchor investor. And if we can do that, the strategy is when you get the anchor investor on board, that anchor investor typically has a number of friends that he or she can then rope into the fold. We're also going to focus more beyond the anchor investment to the smaller potential gifts. We've spent a great deal of our time on the anchor effort. And we will be, as we have successes, reporting in real time back to the board and in the next in-person meeting in March.

“So that's a review of the year. Are there questions? Thank you. That is most definitely a subject to be continued and continued and continued.”

Shilling for Stem Cell Treatments? A Look at the Journal Nature and an Advertising Matter

For UC Davis scientist, Paul Knoepfler it was something "very strange." For Pulitzer Prize-winning Los Angeles Times columnist Michael Hiltzik, it had the earmarks of a "race to the bottom."

And it all involved a stem cell matter published by the prestigious journal Nature.

The headline on Hiltzik's column yesterday summarized the case like this. 

"Did a world-famous science journal become a shill for a questionable stem cell claim?"

Hiltzik wrote,

"Readers of Nature, one of the world’s most important scientific journals, might have been struck recently by an audacious claim appearing on its website about a possible stem cell treatment for heart attacks.

"The published item asserted that MUSE cells, a subset of stem cells, could regenerate heart tissue after acute myocardial infarctions, which are deadly sudden heart attacks. This could be a significant advance in both cardiac treatment and the use of stem cells.

"Here’s the problem. The published item wasn’t a peer-reviewed article subject to Nature’s rigorous professional vetting procedure. It was an advertisement placed by the Translational Research Center for Medical Innovation, the Japanese research lab that says it performed the reported study on MUSE cells using white rabbits.

"It looked like a Nature article, however, at least to Paul Knoepfler, a stem cell expert at UC Davis who has become one of our most assiduous debunkers of stem-cell quackery. Knoepfler thought the layout of the item might cause some readers to mistake it for a peer-reviewed paper, and promptly queried Nature. The journal responded by taking the advertisement offline Feb. 22. Knoepfler’s brief chronicle of the affair can be found on his website here."

Hiltzik concluded:

"The Food and Drug Administration has its hands full monitoring these claims and treatments. The agency has issued multiple warnings to steer the public away from such clinics and has taken administrative and legal action against some of them. The signs point to more exploitation and more danger to the public health. Important journals such as Nature shouldn’t be participating in a race to the bottom."

For the record, Knoepfler has been critical in the past about some of Hiltzik's commentary, including the columnist's views about the state stem cell agency.  

'Getting Stanford's Attention:' The Transcript of a $1.7 Million Matter

The California stem cell agency has posted online the 24-page transcript from last week's meeting during which the agency's governing board raised sharp questions about Stanford University and its obligation to provide co-funding on a $19 million award to one of its scientists.

The board voted unanimously last Thursday to condition additional millions for the research on receiving by May 1 the co-funding, which totals $1.7 million.

Just before casting his vote, Art Torres, vice chairman of the board and a former longtime state lawmaker, said, 

"I do think that we have put forward this motion in order to get Stanford's attention as to what their commitment has been in the past, and what it will continue to be given the nature of the arrangement that we made with them."

Stanford researcher Judith Shizuru sought $6 million for continuation of a phase one clinical trial to develop a potentially "transformative" product that would eliminate the toxic impact of chemotherapy for a number of diseases. 

The $3 billion agency reduced the amount that would be given to Shizuru to $3.75 million along with imposing the deadline for co-funding. 

The agency expects to run out of money for new awards by the end of this year. 

Correction

An early version of the Stanford item today incorrectly reported the deadline for co-funding of the award in question. The correct date is May 1 -- not April 1. Judith Shizuru's last name was also incorrectly spelled. 

California's Stem Cell Agency Smacks Stanford for Failing to Deliver on Financial Promises

The California stem cell agency today delivered an unusual and sharp rebuke to Stanford University, declaring that it needs to stand by its financial commitments to help back state-funded research. 

The message came during consideration of a request for more research cash from a Stanford researcher, Judith Shizuru. She sought $6 million for continuation of a clinical trial to develop a potentially "transformative" product that would eliminate the toxic impact of chemotherapy for a number of diseases. 

"It boggles my mind," said Jeff Sheehy, a member of the agency's governing board and chairman of its Science Committee, that Stanford, which has an endowment of $27 billion, has not stepped forward to provide the co-funding. 

The amount involved is $1.7 million and is due May 1. It is connected to an earlier $19 million award to Shizuru that kicked off her clinical trial. 

Sheehy noted that Stanford and its researchers have received $379 million from the agency since 2005. It is the top recipient of funds from the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. Stanford also has a member on CIRM's board. 

Steve Juelsgaard, chairman of the board's Finance Committee and a former top executive at Genentech, said that Stanford is "very well taken care of in terms of its economics." 

He said that the agency requires all institutions and businesses to sign agreements to deliver on promises of co-funding. CIRM cannot have two standards for its grantees, Juelsgaard said. 

Today was the first time that the $3 billion research agency has publicly rebuked a grantee on co-funding. Recipients of awards, be they institutions or individual researchers, are generally  treated tenderly in public.  (The full transcript of the meeting is available here.)

CIRM directors did not take issue with the quality of the research, which they described as good. Specifically, today's application sought to advance Shizuru's phase one clinical trial to develop a way to avoid the necessity of chemotherapy in a genetic affliction, popularly known as the bubble baby syndrome.

Nine researchers in the field sent letters to the CIRM board praising the work. Several called it "transformative" and said it could have use in afflictions ranging from blood cancer to diabetes. 

Shizuru applied for $6 million. However, the CIRM board reduced the award to $3.7 million and only on the condition that the previous co-funding be delivered.  

Shizuru told the CIRM board she accepted responsibility for raising the co-funding, which she said has been difficult. Board members noted that agreements on awards are signed by both the recipient researcher and his/her insitution. She said she would discuss today's action with Stanford officials.

Her application came before directors in January with a seal of approval from the agency's reviewers, who make their decisions behind closed doors. Normally, approval by reviewers means a rubber stamp by directors.

Action in January, however, was deferred until this month after directors raised questions about research delays and financial matters. The agency also publicly released a slough of information concerning Shizuru's work, most of which she provided to them.  

Here are links to key documents involving Shizuru application. 

• CIRM's news release on today's action
• CIRM's summary of reviewer comments on Shizuru's application, CLIN2-11431. The agency does not disclose the full application.
• CIRM staff's presentation today concerning the application
• Transcript of the January directors' meeting, including a relatively lengthy discussion and comments by Shizuru
• Today's meeting agenda, which includes links to the letters of support, most of them from prominent researchers in the field
• CIRM award details on the $19 million award, including three progress reports 
• Shizuru successful appeal letter on her 2012 application, which had a median score of 50 and was rejected by reviewers. 
• Clinicaltrials.gov information on Shizuru's clinical trial (start date and last update, both Nov. 15, 2016

(An early version of this item misspelled Shizuru's last name.)

A Peek Inside the California Stem Cell Research Machine: $25 Million, Babies, Bonds and Dwindling Cash

California's stem cell agency this week dished up rare public details of an advanced effort to create "transformative" therapies that would help cure afflictions ranging from diabetes to always fatal immune disorders.

The disclosure involves Stanford University researcher Judith Shizuru, severely ill babies, toxic chemical treatments, delays in clinical trials and stem cell agency board members who are acutely aware of the $3 billion agency's rapidly dwindling resources.

Judith Shizuru
Photo by Flynn Larsen, Ludwig Institute

All this plus more is on the table Thursday at a meeting of the directors of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. 

The agenda nominally contains one item, an application by Shizuru for $6 million from CIRM. But the issues reach back to 2013 and provide insight into difficult research pathways and how the agency manages its programs. 

At the top of the matter is the fact that the state agency expects to run out of cash for new awards by the end of this year. It is pinning its hopes on a proposed $5 billion bond measure on the November 2020 ballot.  Meanwhile, directors are trying to raise privately $200 million to tide it over until then. 

Avoiding Toxic Chemotherapy

That was the backdrop Wednesday Jan. 30 when directors convened to consider application number CLIN2-11431 by Shizuru for $6 million. She is seeking a way to avoid chemotherapy treatments and their toxic side effects in the case of a rare genetic affliction often referred to as the bubble baby syndrome. 

In December, CIRM's grant reviewers, meeting behind closed doors, approved Shizuru's application, an action that nearly invariably is rubber-stamped by directors. But last month was different, and a bit of CIRM history was brought up.

Shizuru received  a $19 million CIRM award in 2012 which has led to a phase one clinical trial with positive results for her therapy. Cost per each of the six patients so far averages $917,000, according to a CIRM document. 

However, additional patients are needed, along with more funding, before the potential product can reach the marketplace. The average cost of per patient will run about $333,333 during the final portion of the phase one trial.  Her latest application is aimed providing assistance with those costs. 

Questions about Delays and Co-Funding

Last month, questions arose among directors about months of delays in the clinical trial and a current shortfall in co-funding, among other things.

Steve Juelsgaard

Steve Juelsgaard, a former Genentech executive and chair of the directors' Finance Committee, said, 

"It's not clear to me that they're being frugal with the money that they have been given."

Juelsgaard also said,

"Delay doesn't necessarily add up to more money. They obviously spent the money on something that they didn't anticipate or under-budgeted or something. There's something more to it."

Another director, Jeff Sheehy, chair of the board's Science Committee, said,

"Financially, it seems very muddy to me."

Other directors weighed in as well, ultimately leading to a motion to delay action on the application to provide more time to find answers to questions.

At that point, Shizuru, who was in the audience, rose to respond.

"I understand CIRM's concerns, and I can see you're very thoughtful about how this money is being spent," she said, according to the transcript.

 The Sheehy-Shizuru Exchange

The Stanford researcher said that without additional funding the trial would have to suspend enrollment of additional patients, prompting this exchange between her and Sheehy.

"Shiruzu: Budgetarily we're better off using it (the remaining funding) to continue to follow the patients that we've already transplanted. From that budgetary standpoint, we should delay the trial. We should delay treating any more patients on the trial.

"Sheehy: So Stanford won't front you 1.6 million to (treat) patients if we don't give you the money today?

"Shiziru: I hesitate to say what they would do.

"Sheehy: To Stanford...they would actually put patients at risk?

"Shiziru: I'm not at liberty to say what Stanford would do."

Stanford is the No. 1 recipient of CIRM awards, chalking up $379 million over the past 14 years. It also has always had a member on the CIRM board of directors, who is not allowed to speak or vote on awards to Stanford.

Following Shizuru's comments, CIRM directors approved the motion to delay action until this week's meeting. Since the January session, Shizuru has provided the agency with more than five, single-spaced pages of explanation about her research, plus other material that has been kept under wraps for what CIRM has indicated are proprietary and legal reasons.

The information from Shizuru, as well as additional documents from CIRM, provided an unusual, public look into the agency's grant-making process as well as the hurdles encountered in advanced clinical research. In the past, reviews of applications approved by reviewers have received little or no discussion.

Shizuru's Perspective

In her material, which is available on the agenda for this week's meeting, Shiruzu said one, eight-month delay was caused by CIRM itself because of internal concerns. Another nine-month delay was caused by age-restrictions on patients.

"Significant delay" was also caused because of what might be called a supply and demand issue. The bubble baby syndrome is rare. Only one in out of 50,000 to 100,000 births results in a baby with the affliction: severe combined immunodeficiency.

Three other clinical trials are also competing for those rare patients. 

Nine letters of support were received by CIRM supporting the research, with some describing the potential result as "transformative." The letters also said Shizuru's approach could find use in a wide range of other afflictions, an expectation also agreed upon by CIRM. 

Shizuru said she is working on securing the needed co-funding for her first award, which is not yet concluded. As for commercialization, she said she and her colleagues have formed a company, whose name was not disclosed. She said she has a letter of support from one investor regarding "an intention to co-fund pending completion of due diligence."

In a final comment during the vote last month to delay consideration, one CIRM board member, a San Diego patient advocate for Parkinson's disease, praised the board's close examination of the application. David Higgins said, 

"I want to acknowledge fellow board members (for) their continued concern about spending taxpayer's money wisely because I think this is a great example of that."

(The public can listen to and participate in the Thursday meeting via the Internet. Instructions are on the meeting agenda.) 

California Stem Cell Opposition: Conservative Writer Declares Golden State Efforts a 'Bust'

In a preview of what is likely to be a heated ballot campaign next year,  a conservative writer declared this week that California's efforts to develop stem cell therapies are "a scientific and financial bust." 

"Back in 2004, the $3 billion California Stem Cell Research and Cures Initiative, Proposition 71, promised life-saving cures and therapies for Alzheimer’s, Parkinson’s and other diseases. The cures and therapies, in turn, would send money flowing into state coffers, so the project, in effect, would pay for itself. It didn’t exactly work out that way," said Lloyd Billingsley on two different web sites.  

"CIRM proved itself a scientific and financial bust, and almost completely off limits to state oversight."

Billingsley has written in the past about the agency, known as CIRM and formally as the California Institute for Regenerative Medicine. His latest columns appeared on the California Globe, which was founded by Ken Kurson, who has ties to the Trump family and Rudy Guiliani, and The Beacon.  

Billingsley likened the agency to the troubled bullet train project in California and efforts to solve some of California's water problems by building a tunnel under the California delta east of San Francisco. 

CIRM expects to run out of cash this year for new awards and hopes to survive with voter approval of a proposed, $5 billion bond measure on the November 2020 ballot.

It could be a hard-fought campaign, but conservatives and other likely opponents could well be diverted if President Trump is on the ballot. 

See here and here for more on Kurson, founder of the  California Globe, and here for the advisors to the Beacon web site and its parent organization.

Position of the California Stem Cell Agency on Gene-Edited Babies? No Go.

California's $3 billion stem cell agency may be on the leading edge of regenerative medical research, but it is clearly opposed to the type of work that has led to the international flap over the gene-edited babies in China. 

Its regulations have long barred that sort of experimentation. In 2016, the agency, known formally as the California Institute for Regenerative Medicine (CIRM), convened an international conference to discuss the issues involved.

The session in Los Angeles went on for hours, generating a 223-page transcript touching on the difficulty of regulating gene editing, among a host of other difficult issues. 

One patient advocate in the audience, Adrienne Bell Cors Shapiro, noted that it is nearly impossible to control all that might happen. She said,  

"People are messy. And if you develop this technology, somebody is going to find a way to use it."

Last week the MIT Technology Review published an article about a Stanford University investigation into what two of its researchers knew about the Chinese research. The scientists also have received CIRM funds for research unrelated to the Chinese work. 

Asked for a comment, a spokeswoman for the state stem cell agency said in an email:

"CIRM’s regulations prohibit nuclear genome editing for reproductive purposes. In February 2016, CIRM convened the Scientific and Medical Accountability Standards Working Group (SWG) for a workshop on Human Gene Editing. The SWG subsequently recommended that no changes be made to CIRM’s existing prohibition on nuclear genome editing for reproductive purposes."

In 2016, Hank Greely, a law professor at Stanford who deals with bioethical issues, told the gene editing conference:

"CIRM is in the human embryo experimentation world. It funds research as long as the embryos are not implanted. It funds it with special protections and special review considerations and special informed consent considerations. I don't think CRISPR-cas9 changes that."

The controversial research in China triggered a global uproar in the scientific community. The leading stem cell research organization, the International Society for Stem Cell Research, issued a statement opposing such experimentation. 

He Jiankui, the Chinese scientist who performed the experiment, has lost his job in that country, according to news reports, and may be facing criminal charges. His work has not been confirmed by an independent review. 

California Legislation to Curb Unregulated Stem Cell Clinics Due by March

Legislation to help stem the tide of unregulated stem cell clinics in California is still being drafted, but is inspected to be introduced by the end of this month. 

Art Torres, vice chairman of the California stem cell agency, is working on the measure, which is expected to be authored by Assemblyman Kevin Mullin, D-San Mateo. 

More than 100 dubious stem cell clinics are estimated to be in business in the Golden State, peddling ostensible stem cell treatments that cost thousands of dollars.  The treatments, however, have no scientific proof of efficacy or safety. 

In response to a question, Torres, a former state lawmaker, said that Mullin will introduce legislation that will serve as a placeholder while the legal language is worked out and coordinated with appropriate state agencies.

Torres said in an email, 

"We will have the language ready by March 1 , 2019, to be amended into the spot (placeholder) bill. 

"April 26 is the last day that a policy bill with fiscal implications must be out of the policy committee and referred to the fiscal committee."

The clinics and their treatments are a national issue as well involving the Food ad Drug Administration, which has been slow to move. California legislation is likely to serve as something of a model for other states.

Stanford Probe into Researchers Linked to Gene-edited Babies in China

Stanford University is looking into the involvement of several researchers in connection with the Chinese, gene-edited babies, the MIT Technology Review reported today.

The article by Antonio Regalado said,

"Officials at Stanford University have opened an investigation into what several high-profile faculty members knew about a Chinese effort to create gene-edited babies led by a onetime researcher at the California school, He Jiankui. 

"The investigation, according to people familiar with it, aims to understand what liabilities or risks Stanford may have in connection with the controversial medical experiment, which led last year to the birth of two girls whose genomes had been altered with a molecular tool called CRISPR to render them immune to HIV."

Regalado reported, 

"Stanford launched the investigation following media reports that three of its faculty—more than at any other institution—were aware of He’s plans to create the gene-edited children. They are William Hurlbut, a medical ethicist and theologian who interacted extensively with He over many months; gene-editing specialist Matthew Porteus; and Stephen Quake, a biophysicist who holds a powerful role as co-president of the $600 million Chan Zuckerberg Biohub, as well as being He’s former postdoc advisor."

Porteus has received $7.7 million from the California stem cell agency, formally known as the California Institute for Regenerative Medicine (CIRM). He Jiankui worked from 2010 to 2012 in Quake's lab. Quake is participating in a $40 million genomics program backed by the $3 billion stem cell agency.

Quake has declined comment in the past on his connections to He. Porteus told STAT in December that he had "strongly rebuked" the controversial researcher for what Porteus said was "reckless" work.  Hurlbut has said he had a number of conversations with He and advised him on the moral implications of the work.

Regalado wrote,

"University-led investigations are typically private, toothless affairs with few consequences for important faculty, especially those who pull in millions in grants. The question of research involving human subjects is a critical one, however, in part because serious violations can endanger a university’s federal research grants." 

Roman Reed Act: $5 Million Proposed for More Research into Spinal Cord Injury

Roman Reed discusses stem cell research in 2017

Legislation to provide $5 million for stem cell and other research involving spinal cord injury has been introduced in the California state legislature and is expected to be heard soon in a key committee.

Assemblyman Kevin Mullin, D-San Mateo, introduced the measure that would re-fund the Roman Reed Spinal Cord Injury Research Act. 

Mullin, chair of the Assembly Select Committee on Biotechnology,  said in a news release 

“Sadly, efforts to continue this funding stream that expired in 2011 have failed and critical research in this area has suffered. The absence of state funds has limited the programs ability to attract private investment, limiting the work being done.” 

The news release continued, 

"The Roman Reed Spinal Cord Injury Research Act was originally established in 2000 and was subsequently renewed in 2004. The program, based at the University of California Irvine has continued its work, but on a smaller scale. According to the Reeve-Irvine Research Center, the earlier allocations of approximately $15 million in state funding allowed the program to leverage over $80 million in new grants benefitting virtually all California spinal cord scientists."

The legislation is named after Roman Reed, who suffered a paralyzing spinal cord injury in 1994. He and his father, Don, have been longtime backers of the $3 billion California stem cell agency.  Roman Reed came up with the first slogan of the agency, formally known as the California Institute for Regenerative Medicine (CIRM): "Turning stem cells into cures."

A comment by Don Reed wound up as the title of CIRM's  2018 annual report: "Something better than hope." The senior Reed lobbied the legislature for several years to create the act that ultimately provided the funding for the spinal cord research.

The bill is slated to come before the Assembly Health Committee for its first hearing, perhaps as early as this month. 

A Stem Cell Media Story: The Case of the Missing Mention

Storks and stem cell blessings

California's $3 billion stem cell agency, which is fighting to demonstrate its value proposition, this week received what could be considered some favorable attention in the prestigious journal Nature.

The catch is that the 14-year-old research program was not mentioned by name by Nature.

The question is: How does that work and why it is important?

First things first: It is important because the agency, known formally as the California Institute for Regenerative Medicine (CIRM), is hoping that the voters will bless it with another $5 billion come the November 2020 election.

The agency expects to run out of money for new awards this year and is also trying to raise privately more than $200 million to tide it over until the 2020 election. In both cases, it needs clear successes that demonstrate that it has earned its keep and will do even better in the future. 

Unproven Therapies in Japan

The not-so-odd case from Nature involves an editorial that cited a CIRM-funded clinical trial.  Nature praised it as something to be emulated in Japan as an example of good ethics and good science. 

Nature's editorial zeroed in on how Japan has embarked on "a worrisome approach." The headlines said,  "Japan should put the brakes on stem cell sales. Unproven therapies should not be marketed to patients."

Instead, Nature declared that Japan should focus on the approach taken by Asterias Biotherapeutics, Inc., of Menlo Park, Ca., which arguably owes its existence largely to CIRM. (See here, here and here.)  Nature wrote, 

"Last week, a Californian company called Asterias Biotherapeutics released promising results from a 12-month first phase clinical trial, in which embryonic stem cells are converted into oligodendrocytes — cells of the central nervous system that support neurons and can stimulate their growth — and then injected into the backs of people with a spinal-cord injury. The data show that injected cells do stick around at the injury site, and that most patients (21 out of 22) showed improved movement. 

"But these are still early-stage results. It is not clear yet whether the improvements are the result of the cells, or whether something else, such as the body’s own regenerative capacity, was at work. To find out, the company wants permission to move forward with a randomized, controlled phase II clinical trial. That’s the right way to do things: stepping carefully, slowly and rigorously forward."

It's Not the Stork

The problem for the stem cell agency, of course, is that Nature did not identify CIRM as a player in the Asterias effort, although the agency has pumped more than $20 million into the research. The case of the missing mention is not an unfamiliar situation for the agency, which is often not noticed in news and press releases about the scientific accomplishments that it has backed with tens of millions of dollars. 

Of course, CIRM cannot take full credit for the Asterias work. And federal regulators have rules for clinical trials. But CIRM put up the cash for the research after Asterias' predecessor bailed out.  The agency also partners closely with its grantees and has a clear set of pioneering research standards that it worked out more than a decade ago. 

Obviously, CIRM would have been only a brief note, perhaps only a phrase in the Nature editorial if it had decided to include a mention. But these things add up and are needed by CIRM as it tries to tell California voters that it has been worth $3 billion. Their absence can amount ultimately to a substantial negative. 

One does not have to support more cash for CIRM to recognize that California voters need the full array of information about the agency to make an informed decision in 2020. Currently, however, the traditions and practices of scientific journalism regularly omit significant financial information.

When one reads about scientific advances in the mainstream media as well as journals, it seems as if the research magically materializes without a critical insemination of cash -- much like a baby being brought by the stork.

Perhaps it is time for CIRM, other research funding agencies and patient advocates to have a facts-of-life "talk" with the scientific press about the reality of what it takes to give birth to prodigious medical advances.

(Editor's note: Here is a related item by UC Davis stem cell research Paul Knoepfler on the Japanese program.)

California Stem Cell Agency Approves Assault on "Terrorizing" Affliction: Huntington's Disease

Frances Saldana, at a stem cell agency meeting last year, spoke emotionally about the loss of her three children to Huntington's disease. 

Directors of the California stem cell agency this morning approved $18 million in clinical stage research awards, including a "high risk" plan to tackle a degenerative brain disease for which there is no treatment.

Action on the proposal to create a therapy for the genetic disorder, Huntington's disease, came after a woman who lost all of her three children to the affliction said it has "terrorized my family for generations."

Frances Saldana of Fountain Valley, Ca., wept as she pleaded for approval of the $6 million effort to treat the disease that  lingers in her family. 

Another patient advocate, Bill Waddington, whose mother died from the affliction, told the agency in a letter, 

"Huntington’s disease isn’t just death.  It’s complete and utter devastation to families."

Maria Millan, president of the stem cell agency, said later in a news release that children born to parents with Huntington's have a 50/50 chance of getting the disease.

Huntington's affects 30,000 persons with another 200,000 at risk. It  progresses slowly. Symptoms are unrelenting and include inability to control movement and declining cognition leading to dementia, according to experts. Affected persons usually die within 15 to 20 years after diagnosis,. 

The applicant for state stem cell funding, Leslie Thompson of UC Irvine, told the board in a letter,

Leslie Thompson
UC Irvine photo

"Given the relatively slow progression of HD, care-giving stretches over 10 years or more after the patient loses independence. Patients become completely dependent on family and caregivers, who in turn have an emotional and debilitating economic burden managing the physical, cognitive and psychiatric manifestations of the disease.  

"HD can lead to catastrophic events such as homelessness, prolonged hospitalization awaiting placement, or long-term psychiatric placement. The length and severity of the disease has a profound financial and emotional impact on families and health systems. The direct medical costs and costs of disability and care giving for each patient are substantial and pass from one generation to the next."

Members of the governing board of the agency, formally known as the California Institute for Regenerative Medicine (CIRM), discussed the application at some length because of a split involving the application reviewers. The summary of comments by reviewers said,

"Reviewers disagreed on whether the treatment offers a significant value to the patients and caregivers. Some reviewers thought the immunosuppression and surgical risk that is required for this cell therapy may outweigh any potential therapeutic benefits given that there are other less invasive treatment options being tested. Others thought that despite the stated risks, any potential treatment for slowing down disease progression is worth pursuing as current alternative therapeutic approaches are still many years away from commercial use."

Last month, the agency's reviewers, meeting behind closed doors, approved the award on an 8-1-5 vote with five against funding, eight for funding and one saying the application needs improvement and could be resubmitted. The latest application was, in fact, a resubmission after changes were made to deal with reviewers' concerns.  The summary of the latest version described the effort as "high risk."

In one of the six letters of support for Thompson's research, Michael West, CEO of AgeX Therapeutics, Inc., of Alameda, Ca., said the work could have application in treatment of other neurodegenerative diseases such as Alzheimers and Parkinson's.

Six is a relatively high number of letters for the board to receive on an application.  Advocates dealing with Huntington's have been active in the past, appearing before the CIRM board on a number of occasions.

The second award today went to Everett Meyer of Stanford and totalled $12 million. It involves a clinical trial for renal failure. 

Here are links to review summaries for each application considered today, the principal investigator, institution and other information. 

Application number, CLIN1-10953; amount, $6.0 million; title, "An hESC-derived hNSC Therapeutic for Huntington’s Disease;" principal investigator, Leslie Thompson; institution, UC Irvine; review summary; letters of support, letter to the board CLIN1-10953, letter to the board #2 CLIN1-10953,​ letter to the board #3 CLIN1-10953, letter to the board #4 CLIN1-10953, letter to the board #5 CLIN1-10953, letter to the board #6 CLIN1-10953, letter to the board CLIN2-11431, other CIRM funding for the PI, $12 million.

Application number, CLIN2-11400; amount, $12.0 million; title, "Induction of Tolerance by Combinatorial Therapy w/ Donor Stem Cells and Expanded Recipient Treg cells in HLA-mismatched Kidney Transplant Recipients;" principal investigator, Everett Meyer; institution, Stanford; review summary; letters of support, none; other CIRM funding for the PI, none.

Action on the following application was put off until Feb. 21 to provide time to answer financial questions raised by board members today: 
Application number, CLIN2-11431; amount, $6.0 million; title, "A monoclonal antibody that depletes blood stem cells and enables chemotherapy free transplants;" principal investigator, Judith Shizuru; institution, Stanford; review summary; one letter of support; other CIRM funding for the PI, $20.4 million.

California Stem Cell Agency to Award $24 Million for Three Clinical Trials

If all goes according to plan, in just three days the California stem cell agency will be down to its last $69 million for clinical trials.

Directors are set to give away $24 million on Wednesday for three clinical trial programs as the agency runs out of cash this year for new awards. The agency started with $3 billion 14 years ago. It has allotted $144 million for research awards this year.

The agency, known formally as the California Institute for Regenerative Medicine (CIRM), is attempting to raise privately more than $200 million this year. It is also hoping that voters will approve $5 billion more in funding in the November 2020 election. 

Applications coming before directors this week involve $6 million for Huntington's disease, $6 million for immunodeficiency studies and $12 million for renal failure research. 

The agency withholds the names of researchers and institutions involved until directors act publicly.  The agency's reviewers earlier approved the applications during a closed door session. The agency board almost never overturns the decision of its reviewers. 

The public can participate in the teleconference meeting via the Internet. Instructions can be found on the meeting agenda along with summaries of the reviewers comments on the applications.

CIRM was created by California voters in 2004 and provided with $3 billion in bond funding. No other significant source of income was provided under the ballot initiative.

Correction: An earlier version of this item that was up briefly incorrectly described the $69 million as all that remained for all awards this year.