Parkinson's and the Unseen Offspring of California's Stem Cell Agency

On the surface, Aspen Neurosciences, Inc., a tiny firm in La Jolla, Ca., does not seem to have much of a connection to California's $3 billion stem cell agency.

It is not alone. A good chunk of the collateral benefits of agency is all but invisible. While the agency's web site is chock-a-block with videos, statistics, testimonials and pie charts, not everything significant rises to the top. Most of the information can be classified as high profile. Aspen, however, is barely a footnote for the agency. 

 

Yet the firm, over the last six months, has received a $76 million validation from the private sector, more than any business has received from the California Institute for Regenerative Medicine (CIRM), as the stem cell agency is formally known. Viacyte, Inc., of San Diego, is No. 1 among the business beneficiaries of CIRM, collecting $72.3 million.  

The lack of visibility of some benefits from CIRM may not seem all that important to some. But when plans are afoot to ask California voters for $5.5 billion to forestall the financial demise of the stem cell agency, voter perceptions of the agency become paramount. 

Aspen's story has elements that could resonate with many voters. It involves a well-regarded woman scientist, pursuit of millions of dollars, failures and success and patients with stories of their terrible times with a dreadful affliction.  

The tale begins within walking distance of what is now Aspen's headquarters in La Jolla. Aspen is located just down the street from the Scripps Research Institute, where Jeanne Loring was director of the Center for Regenerative Medicine and who also earlier co-founded a firm that morphed into Viacyte. 

While she was at Scripps, she embarked on research aimed at Parkinson's Disease, stimulated and aided by a patient advocacy group called Summit for Stem Cell. It is an energetic group and once collected $120,000 in a fundraising effort that took nine Parkinson's patients on a hike at Machu Pichu in Peru. 

Summit members also trekked to meetings of the governing board of the stem cell agency to build a case -- sometimes with tears and trembling voices -- for more money and more speed on Parkinson's research. (See here also.)

Loring filed for grants for her research as well. She ultimately collected nearly $22 million from CIRM, but the agency did not follow through on additional applications. Loring cast about for other possibilities, and she and Andres Bratt-Leal, also of Scripps and Summit for Stem Cell, co-founded Aspen Neurosciences. 

Loring strongly supports renewing the financially endangered stem cell agency with $5.5 billion. She has told the California Stem Cell Report, 

"All of my CIRM awards contributed to (Aspen). We used those funds to develop our genomics tools and databases and to develop improved methods for handling the cells." 

Loring is now Aspen's chief scientific officer. Bratt-LealHer is vice president of research and development. Their ongoing work now at Aspen is aimed at creating the "first autologous neuron replacement therapy to treat Parkinson's disease," Aspen said in a news release. 

Aspen expects to use its private financing to launch a phase one trial for the therapy, which begins with a patient's own skin cells. They are reprogrammed to become pluripotent and converted into neurons. The neurons are transplanted into a patient to replace the ones that Parkinson's has destroyed. 

Whether Aspen can produce a commercial treatment that is widely available remains to be seen. Whether CIRM's supporters can produce a $5.5 billion victory in November remains to be seen as well. It is likely to depend entirely on how voters see the benefits of CIRM's work over the last 15 years -- invisible and otherwise. 

(Note to readers: If you know of other unseen offspring of the stem cell agency -- good or bad -- please send a note to djensen@californiastemcellreport.com. Your emails will be held in confidence. Thank you.)

(After this item was posted, the agency posted a blog item dealing with Parkinson's. In addition to information on the search for a cure or treatment, the item carried the following advice for persons seeking some sort of unregulated treatment. Here is what the agency had to say in a Q&A format,

"If you go online you can find lots of stem cells clinics, all over the US, that claim they can use stem cells to help people with Parkinson’s. Should I go to them?

("In a word, no! These clinics offer a wide variety of therapies using different kinds of cells or tissues (including the patient’s own blood or fat cells) but they have one thing in common; none of these therapies have been tested in a clinical trial to show they are even safe, let alone effective. These clinics also charge thousands, sometimes tens of thousands of dollars these therapies, and because it’s not covered by insurance this all comes out of the patient’s pocket.

("These predatory clinics are peddling hope, but are unable to back it up with any proof it will work. They frequently have slick, well-designed websites, and  'testimonials' from satisfied customers. But if they really had a treatment for Parkinson’s they wouldn’t be running clinics out of shopping malls, they’d be operating huge medical centers because the worldwide need for an effective therapy is so great.

("Here’s a link to the page on our website that can help you decide if a clinical trial or “therapy” is right for you.")

A Covid-19 Success, 300 Percent Stock Price Increase and the California Stem Cell Agency

A company that the California stem cell agency has backed with nearly $18 million scored big this morning on news that one of its products had generated a 100 percent survival rate with a small group of critically ill Covid-19 patients.

The company is Capricor, Inc., a publicly traded company based in Beverly Hills, Ca. Its stock soared more than 320 percent at one point this morning from its previous close of $2.41 based on the news about its CAP-1002 therapy. Shares stood at $9.09 at the time of this writing.  

The company said in a news release that it had generated "100 percent survival in critical Covid-19 patients who were treated with Capricor’s lead asset, off-the-shelf ('allogeneic') cardiac cell therapy CAP-1002, at Cedars-Sinai Medical Center as part of six compassionate care cases." 

The company said the federal government has approved 20 additional patients for treatment. Capricor also said it is developing "a randomized, placebo-controlled trial planned to treat patients with moderate and severe disease which is intended to be funded by non-equity capital."

Capricor and its underlying research have long been embedded with the state stem cell agency, which is formally known as the California Institute for Regenerative Medicine (CIRM). In addition to $17.8 million given directly to the company, another $7 million went to Cedars-Sinai for much of the early development work that led to the creation of Capricor. 

Speaking to the agency's governing board in 2016 concerning CAP-1002, CIRM director Jeff Sheehy, chair of its Science Committee, said, 

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

In 2018, a clinical trial involving CAP-1002 was begun at UC Davis as part of CIRM's separate Alpha Clinics program, an ambitious statewide effort to lead the way nationally on stem cell research.

In a news release this morning, Linda Marban, CEO of Capricor, said, 

"As the global medical community continues to come together in its battle against COVID-19, the results of our initial compassionate care cases are extremely promising and what we had anticipated. We look forward to continuing to treat additional patients under our recently approved expanded access program Investigational New Drug application.

“CAP-1002 is an easy-to-deliver intravenous therapy that has been administered successfully to over 150 patients to date. Given its novel mechanism of action, it could be a potential game-changer in helping countless Covid-19 patients.”

The Capricor product initially targeted Duchenne muscular dystrophy (DMD), "a muscle wasting condition that steadily destroys the muscles in the arms and legs, heart and respiratory system" of boys and "never lets up," CIRM says.

The CAP-1002 treatment has demonstrated immunomodulatory properties that come into play with Covid-19. Capricor said, 

"Multiple published peer-reviewed studies of CDCs have demonstrated favorable modulation of various inflammatory cytokines and regulation of the immune response. The current understanding of Covid-19’s later stages are thought to be due to overstimulation of the immune system, which triggers a cytokine storm in which the body is overwhelmed with pro-inflammatory molecules. This immune response may become excessive and pathologic, inducing pneumonia, organ failure and death. Therefore, it can be the body's overreaction to Covid-19, rather than the virus itself, that delivers the fatal blow."

Capricor is also working on a Covid-19 vaccine involving a different technology.

The $22,000-an-Hour California Stem Cell Story: Rosy Expectations, Fuzzy Future

Evangelina Padilla Vaccaro
CIRM photo

Highlights
Trump and state bond issue?
More than 60 clinical trials projected

No therapies yet for general public
Siren appeal for reseachers
$2.2 billion out the door

Evangelina Padilla Vaccaro – a pink bow in her hair – was likely the first four-year-old ever to address the leaders of California’s $3 billion stem cell research program.

“Thank you,” she whispered. Her mother said more: "Thank you for keeping my family complete." 

Alysia PadillaVaccaro’s voice cracked, and tears flowed on that cool December morning at the meeting at an Oakland hotel.

Evangelina had much to be thankful for. She was born with “bubble baby” syndrome, which meant that she had no functioning immune system. Scientist Donald Kohn of UCLA cured her of the rare affliction by using her own blood stem cells to alter a troublesome gene. It was an experimental treatment not readily available to the public at large. Kohn’s research has been heavily supported with nearly $52 million by the state stem cell agency, known formally as the California Institute for Regenerative Medicine (CIRM) .

Evangelina’s story is just what Californians hoped for when they created the Oakland-based agency in 2004 via Proposition 71. Voters were told that stem cell therapies would ease afflictions found in nearly 50 percent of California families. The agency would create the “cures for tomorrow,” said then Gov. Arnold Schwarzenegger.

Since its first awards in 2005, the agency has given away money at a rate of $22,000 an hour, seven days a week, 24 hours a day. But it has yet to come up with a therapy that reaches the general public despite rosy expectations raised by the ballot campaign.

Today, the future of the program is unclear. The agency calculates that it will run out of cash in just three years. Whether it lives on could depend on the likelihood of another multibillion-dollar bond issue, not to mention the success – or the lack of success – of as many as 60 or more clinical trials and even the policies of the newly elected president of the United States, Donald Trump.

Stem cell therapies, it turns out, are expensive and difficult to bring to market, and their use may be

Shinya Yamanaka, UCSF photo

limited to a handful of diseases. On Monday, Nobel Prize winning stem cell scientist Shinya

Yamanaka said as much in an interview with Wallace Ravven of The New York Times. Because of a wide variety of constraints, he said, 

“We can help just a small portion of patients with stem cell therapy.”

In this context, heartwarming stories of patients such as Evangelina could be some of the strongest selling points for CIRM’s continued existence. They could fire the enthusiasm of voters and embolden businesses to partner with CIRM to bring therapies into the marketplace. The number of these emotional stories is increasing.

Evangelina was not alone at the CIRM meeting last month. Three more patients stepped up during a look at the agency’s performance. They included a 22-year-old man, also with a rare, immune-deficiency disease, a paralyzed 19-year-old man and a 70-year-old cancer patient -- all of whom had experienced major improvements during clinical trials. All told, the agency has pumped $113 million into the research that has benefited the four patients.

Evangelina’s story had special significance for Jan Nolta, head of the UC Davis stem cell program.

Jan Nolta, UCD photo

Nolta began her career working with Donald Kohn at Childrens Hospital in Los Angeles in early research involving the “bubble baby” affliction.

“CIRM has funded Don’s continued work in this area, and he has now functionally cured over 20 children with this disease,” she said in an email. “These kids now need no expensive medicine and treatments to keep them alive. They are functionally cured.” 

In Evangelina’s case, she was able to join her fraternal twin sister, Annabella, in living a normal childhood.

CIRM funding has also fueled the growth of the UC Davis stem cell program, which barely existed prior to creation of the stem cell agency. Today Davis has chalked up $129 million from the agency. “We have 16 stem cell or regenerative medicine clinical trials ongoing or recently completed, with more than 20 in the pipeline,” Nolta said.

Davis ranks as the No. 5 recipient of funds from the agency, trailing only such institutions as Stanford, $314 million; UCLA, $269 million; UC San Diego, $170 million, and UC San Francisco, $139 million.

Nolta is one of a number of researchers attracted by CIRM, lured by the cash and research environment created by the stem cell agency. program. She returned to California from Washington University in St. Louis. (See the full text of Nolta's remarks here.)

The appeal of the California largess was highlighted last week by George Daley, dean of the Harvard Medical School.  He was quoted in a lengthy piece about San Francisco Bay Area biotech written by STAT news service editor Charles Piller.

"'I’ve been looking at this from the outside, and franly have been very envious as a scientist based in Massachusetts,' Daley said. CIRM funds have turned many research centers in California, including UCSF, into world leaders in stem cell science, he said, adding: 'I heard the siren song of CIRM early. I considered making a move,' as did more than two dozen of his Harvard stem cell colleagues."

Since CIRM’s inception, it has awarded $2.2 billion to 853 California researchers and institutions. It estimates that it will award another $692 million before money runs out. This year it plans to give away $328 million.  (The awards are separate from the agency’s operational budget, which is capped by the ballot initiative and is about $19 million for the current fiscal year.)

Like most other recipient institutions, UC Davis has representation on the CIRM governing board. The California Stem Cell Report, which has monitored the agency since 2005, has calculated that about 90 percent of the agency’s cash has gone to institutions with links to past or present board members. Those members are barred from voting on awards to their institutions, but they do vote on the nature of the award rounds and approve the rules.

Concerns about conflicts of interest have long been a bugaboo for the agency. Last September,The Sacramento Bee reported that its former president, Alan Trounson, received $443,500 in total compensation after being named in 2014 to the board of directors of StemCells, Inc., of Newark, Ca. Trounson’s appointment to the company’s board came only seven days after he left the agency at the end of June 2014.

Randy Mills, FDA photo

Trounson was replaced by C. Randal Mills, who had been president of Osiris Therapeutics, Inc., of Maryland. Under Mills’ leadership, Osiris was the first company in the world to commercialize a stem cell drug, qualifying it for use in Canada.

Mills and the CIRM team – currently comprised of 48 people – re-crafted the agency’s objectives and established measurable benchmarks for success, winning board approval for what Mills called radical change. The results were summarized at last month’s board meeting and in the 2016 annual report. They included:

• Over the last two years, the agency has helped to finance 27 clinical trials and is looking for another 40 by 2020. (Clinical trials are the last stage before a therapy is approved by the Food and Drug Administration (FDA) for widespread use. Only one out of 10 conventional drug products emerge successfully from the trials.)

• More than 250 projects are currently being managed by the CIRM team.

• Twelve "world-class" research facilities have been created over the last 12 years.

• Three Alpha Clinics, intended to be one-stop stem cell centers, are in operation. A fourth is scheduled for this year.

• A $30 million stem cell "pitching machine" to speed clinical trials and help guide development through federal regulations began operations in 2016.

Nonetheless, development of stem cell therapies -- much less cures -- is a risky business and could be stymied by a number of issues. The agency itself acknowledges risk factors that include reluctance by businesses to invest in stem cell therapies and safety concerns, including the possible death of a patient in a clinical trial.

Mills makes a practice of presenting risk, an innovation at the agency, as he offers up new programs to its governing board. In the annual report, he quoted the poet T.S. Eliot as saying,

“Only those who will risk going too far can possibly find out how far one can go.”

The agency has experienced a few hiccups since Mills arrived. He acknowledges he is still working hard on attracting businesses to partner with scientists to turn their research into cures. 

An ambitious effort to create a unique, public-private, $150 million enterprise to develop stem cell therapies and cures stumbled late last year when no qualified applicants surfaced from the private sector. The agency hopes to recast the proposal in such a manner that it will find a partner.

One of those watching the agency since its beginning is Hank Greely, director of the Center for Law

Hank Greely, Stanford Law photo

and the Biosciences at Stanford.

He said in an email,

“CIRM has been spending money from Proposition. 71 for about 10 years. Once initial hopes of finding low-hanging fruit disappeared, this kind of slog toward treatments became inevitable.  (Although, in biomedicine, 10 years is not (Greely's boldface) a long time - see the 35 plus years it has taken gene therapy to get to the edge of an FDA-approved product.)

“The next few years should determine just how good California's investment has been. It is encouraging to see CIRM supporting so many clinical trials; it will be much more exciting when – and I do expect ‘when’ and not ‘if’ – one of those trials leads to an approved treatment.” 

John M. Simpson of Consumer Watchdog of Santa Monica, Ca., has also observed the agency for years. He said in an email,

“CIRM’s fundamental problem is that supporters of Proposition 71 wildly oversold what passage of the measure would deliver. Voters were led to believe that miraculous cures were just around the corner if only the proposition passed.

“CIRM-funded research has made important contributions to science, but has yet to deliver what voters were promised,” Simpson said. He added that agency management has improved under the regime of CIRM Chairman Jonathan Thomas and Mills “and the most blatant conflicts of interest were mitigated after the scathing Institute of Medicine report.”

In 2012, the highly respected Institute of Medicine, in a $700,000 report commissioned by the agency, recommended sweeping changes at CIRM to deal with conflicts of interest, its dual executive arrangement and the composition of its governing board. The CIRM board initially greeted the report coldly but made some changes to deal with the critical findings.

California patient advocate Don C. Reed, who campaigned for stem cell research long before CIRM surfaced, however, hailed the agency's work as already saving lives and creating hope for millions. He said in an email it was a "quiet triumph" that can be built on. (See here for full text.)

Simpson, who was heavily involved in development of the agency’s intellectual property policy,

John M. Simpson
 Consumer Watchdog photo

raised questions about the failure of the agency to generate the $1.1 billion in royalties for the state promised by its backers. Simpson said,

“The CIRM annual report cites the number of ‘inventions’ CIRM has funded — more than 180.  What share of royalties have taxpayers received as a result? Anticipated revenue from CIRM-funded inventions was a big selling point for Proposition 71.”

(See here for the full text of Simpson's comments.)

 Ironically, another selling point for the ballot measure came inadvertently from former President George Bush, who had restricted federal funding for human embryonic stem cell research. Backers of the ballot measure said it was needed to compensate for Bush’s action. His restrictions were lifted by President Obama. But many researchers are worried that the Trump administration will once again limit federal support for stem cell research.

Stanford’s Greely said,

“The election of Donald Trump and the continuation of a Republican-controlled Congress could create an increased need for extending CIRM.  If the federal government pulls out of some research on basically religious grounds, California may want to step in again.  It depends both on exactly how restrictive the federal government becomes and, more subtly, on how promising the stem cell trials appear.

“I suspect some federal funding restrictions are inevitable but their scope is unpredictable. As to the trials, if they are tremendously exciting, private funds might take over; if they flop, state funds may not be appropriate.  But if the results are very promising but not spectacular, more state funding might be invaluable.” 

(For more on a possible bond election and Trump's position, see here, here, here and here.)

Simpson has another view. He said,

“No doubt CIRM-funded research has made some important contributions to scientific knowledge. The results, however, in no way justify another bond issue to fund the agency.  If CIRM continues after the current funds run out, it should be financed like any other state agency— out of the state’s operating budget approved by the Legislature on annual basis. CIRM’s operating budget could also be augmented by private contributions.”

Mills avoids public discussion of such things as bond measures. But at a meeting last fall, he likened the research program to a “giant flywheel.”

“It takes a long time to get started, and you move it imperceptibly. Once that thing gets turning, it's almost impossible to stop.”

(Editor's note: A shorter version of this story can be found in the print edition of The Sacramento Bee for Jan. 17, 2017, and also on The Bee's website. The full text of various comments follows this story, which also has links to them. Greely's complete comments were included in the article above.)

(On Jan. 19, STAT news carried a lengthy piece on the agency that said it was slow in financing clinical trials, a major factor that has hampered development of a therapy.)

(An earlier version of this item also incorrectly stated Evangelina's age.)

$32 Million Project: California Opens Largest Public Stem Cell Bank in World

Stem cell storage tanks at new stem cell bank -- Coriell photo

Highlights
300 different stem cell lines
3,000 donors
Coriell, CDI operating, supplying
Stanford, UCLA, UCSF and UCSD involved

Thanks to the taxpayers of California, the Golden State is now home to the largest publicly available stem cell bank in the world.

The state’s $3 billion stem cell agency this morning announced that the bank, located in Marin County north of San Francisco, is open for business.

The project is backed by $32.3 million from the California Institute of Regenerative Medicine (CIRM), as the agency is formally known.

In a news release this morning, CIRM said the bank is “offering the first 300 different stem cell lines for researchers interested in gaining a deeper understanding of, and developing treatments for 11 common diseases and disorders.”

The agency said the bank, housed at the Buck Institute in Novato, is collecting samples from as many as 3,000 donors. CIRM said,

“Those samples will then be turned into high quality stem cell lines – known as induced pluripotent stem cells or iPSCs – which are available to researchers throughout California and the rest of the world.” 

CIRM Chairman Jonathan Thomas said,

“We believe the bank will be an extraordinarily important resource in helping advance the use of stem cell tools for the study of diseases and finding new ways to treat them.” 

As of this writing, the announcement had received coverage on the San Francisco SFgate Web site and on other sites in the San Francisco Bay Area that are owned a news media chain and another site in Pennsylvania.  The coverage is likely to grow throughout the day, which is important to the agency. It is hard-pressed to generate news coverage for its achievements. 

The bank was funded by awards from California in 2013 and is operated by the non-profit Coriell Institute of Camden, N.J.  Generation of the cells is performed by Cellular Dynamics International, Inc., of Madison, Wisc.

CDI was formed by stem cell pioneer research Jamie Thomson of the University of Wisconsin. It was sold to Fujifilm of Japan earlier this year for $307 million at double its stock price.

Also involved in securing the initial adult cells are researchers at UC San Diego, Stanford, UC San Francisco and UCLA.

Here are links to the press releases at Coriell and CDI. Here is a link to a summary of the CIRM banking initiative and a link to a progress report on the effort. Below is a list of participants and amounts of awards. Click on it to see it in a larger format.