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.