On the threshold of cell therapy for Parkinson’s disease

By Jeanne Loring

Dopamine neurons derived from a Parkinson's disease patient's iPSCs (Tyrosine hydroxylase)
Dopamine neurons derived from a Parkinson’s disease patient’s iPSCs (Tyrosine hydroxylase). Image source: Loring lab.

There are ten million people in the world who have Parkinson’s disease. 125,000 of these are living in California.  People with the disease often have to step away from their jobs because the main symptoms – tremor or freezing up of muscles – make it difficult to get through a whole day of work.

Parkinson’s disease is caused by the loss of a specific neuron type in the brain.  The dopamine neurons in the region of the brain called the substantia nigra die over time, and by the time the disease is diagnosed, at least half are gone.  There is no drug therapy that can bring them back.

Because a single cell type in a specific area of the body is lost, it has long been argued that Parkinson’s disease is the ideal target for a cell replacement therapy using dopamine neurons derived from embryonic or induced pluripotent stem cells.

That is exactly the strategy quickly moving forward right now by four research groups worldwide, who have joined forces to share their information in an initiative called “GForce-PD”.

GForce was started in 2014 by three research groups:  Jun Takahashi (Japan) a partnership between Roger Barker (UK) and Malin Parmar (Sweden), and Lorenz Studer (New York).

A new report describes the results of the GForce meeting in May of this year in Kyoto: “Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson’s Disease: Dawn of a New Era”. Our program (called “Summit”) is included along with the other three in the report.

My team was delighted to be invited to join G-Force this year at the Kyoto meeting to contribute our own neuron replacement therapy program to the initiative. While the other groups are using allogeneic (unmatched) cells and will give the patients immunosuppressive drugs, we plan to use patient-specific (autologous) iPSCs to make neurons for each patient, which will keep the cells from being rejected.  Our project was started in 2011 with funding from hundreds of people who donated to the Summit for Stem Cell Foundation and a grant from the National Stem Cell Foundation, and we recently were awarded a grant from the California Institute for Regenerative Medicine (CIRM).

The Kyoto meeting was unprecedented in my experience.  Instead of competing, the four groups cooperated and shared plans for their proposed clinical trials.  We agreed to harmonize our trials and stay in communication about our progress.  All of us plan to start clinical trials within two years.

Support for GForce projects

Each of the GForce members has to obtain independent support from his or her own funding agencies.

NYSTEM, New York’s stem cell agency, has invested about $23 million, nearly 7% of its total budget to date ($354 million) in Lorenz Studer’s program to use hESCs to produce dopamine neurons from human embryonic stem cells (hESCs) for transplantation (allogeneic therapy).  This year Studer and a Toronto investigator founded a company, BlueRock Therapeutics, with a remarkable investment of $225 million that will pay for the planned clinical trials.

The UK/Sweden project has been supported with more than $27 million from the European Union (EU)(http://cordis.europa.eu/project/rcn/94248_en.html; http://cordis.europa.eu/project/rcn/110638_en.html), in addition to funds from other agencies.  They are also using hESCs (allogeneic therapy).

Specific funding for the Japanese project is not reported, but it is part of CiRA, the stem cell institute headed by Dr. Shinya Yamanaka, that receives hundreds of millions from the Japanese government. Again, this project is using allogeneic therapy, with iPSCs from a single individual.

Unfortunately, CIRM has not provided nearly as much support for Parkinson’s disease therapy as the other agencies.  Although CIRM has invested in California scientists for basic research to study PD over the last 10 years, it wasn’t until a year ago that they finally funded a grant for development of a stem cell-based PD therapy.  Our CIRM grant to develop an autologous therapy is for $2.3 million, a tenth as much as the other GForce projects and less than one percent of CIRM’s total $3 billion budget.

Since my team has been recognized by the international GForce initiative devoted to safe effective therapy for PD, we hope that CIRM will follow the example of New York, the EU, and Japan, and invest more in our project to provide neuron replacement therapy for Californians with Parkinson’s disease.

While we hope to gain more support from CIRM, we are determined to follow through with our clinical trial, with or without CIRM.  It will just be more difficult without their help. The patients and their advocates inspire us, and we won’t let them down.

7 thoughts on “On the threshold of cell therapy for Parkinson’s disease”

  1. Hi Jeanne – thx for the feedback and the vested perspective on CIRM’s grant making process over the years. I suppose one dedicated institution can’t & couldn’t realistically underwrite all worthy CA programs but I do believe the strategy to build a vertical support structure from the ground up and investing in a proprietary ROI criteria rather than a public outcome evaluation mechanism & driving real world data has led to an unattainable Camelot syndrome mentality. The public exception perhaps are the Alpha Clinics which may be the most visible legacy program that if pushed further and modelled for state-to-state best practice adoption would be of great benefit to the sector (as I opinioned with JT back in ’13). I do hope there’s a mainstream unmet disease condition which successfully passes a clinical phase II or better yet a phase III with breakthrough results, that CIRM funding was instrumental in supporting, which the agency can present to the public by 2020 – PK would certainly seem to be a key indication to score a goal in.

    All the best, as always.


  2. Hi Michael:

    It’s always a pleasure to hear from you. In an attempt to answer your questions, here are a few thoughts.
    Indeed, many applicants have complained about CIRM’s choices of which grants to fund…in the CIRM 1.0 days, during Alan Trounson’s tenure, a lot of companies applied and, with a couple of exceptions, there seemed to be a bias against them. Randy Mills’ remake, CIRM 2.0, appears to have the opposite preference, for companies, and many of the disease team awards started as academic groups under CIRM 1.0 and morphed into companies for CIRM 2.0’s clinical phase translational grants. Having been in both academics and biotechnology, I don’t see any clear reason to choose one over the other. Some companies are bad at translation and some academic labs are good at it.

    What impressed me most about CIRM 2.0 was Randy’s train metaphor- researchers welcomed the idea that once we were “on the train” with an early stage grant, CIRM would support our progression to the next “car” in the train…from discovery to translation to clinical. Under 1.0, getting grants was a “whack a mole” game (Randy’s term, not mine), with success in one phase of a project having no effect at all on the odds of getting the next phase.

    I’ve had more CIRM grants than most – 9 as a principal investigator, 3 as a co-investigator, and several more as a collaborator, but I had an advantage- when CIRM started, I already had experience with hESCs and funding from the NIH for hESCs, because of being included on Bush’s approved hESC list.

    But the Parkinson’s disease program has been remarkably challenging for me with regard to CIRM. We had to try multiple times before we got out first CIRM PD grant and have no expectation that it will get easier.

    From the earliest planning stages, we decided to use autologous iPSCs. We knew that it would be a challenge as a new approach for the FDA to consider, but we also understood that it was the best possible way to a successful therapy without the requirement for immunosuppression. Now we’re on the threshold, with solid data on the quality and safety of DA neurons from 10 Parkinson’s patients, and a plan to have our pre-IND meeting with the FDA within the next few months.

    It would be great if CIRM decides to use us as an opportunity to have a California-grown PD therapy succeed, but my team, with the help of patient advocates and donors, has built a plan to move forward both scientifically and financially, and we will move forward no matter what CIRM decides. We could however, move more quickly if we are on CIRM’s train.

  3. Hi Jeanne

    Thx – great G-Force update piece with colleagues from the frontline of PD translational research. Also positive momentum vibes from the interim safety read-out just now in the 1st pluripotent trial for PD happening in Australia by that, shhh don’t mention their name, die-hard California stem company down the road from you in San Diego (https://msemporda.blogspot.com/2017/11/parthenotes-flying-under-radar-of.html).

    My question is regarding the Auto versus Allo issue. All the pluripotent approaches are favoring an Allo approach, I guess for a reason(s), whereas your program is Auto. Is there a specific backstory to that related to the foundation behind your program or was it a deliberate choice? As you know I’m for anything that works to address unmet medical needs, including tailoring cutting edge science for one-off personalized treatments – i.e. your analogy to immunotherapy approaches to cancer. Also, are there any trade offs with regard to using older cells versus the potential for Allo compatibility issues.

    CIRM is a indeed a topic, not one for the textbooks it seems when it comes to the How and Why. I recall someone relaying that Mike West/Caldwell/Lanza, of Advanced Cell Tech days (later Ocata – love that name btw! lol) put forward 19 applications for support funding and all were rejected. True? Geron was the shoe-in story then, as was Stem Cells Inc later… If they were actually ahead of the curve an early in with a CAR-T program could have been worth more than they owe the state now…

    If you asked me money granted your lab and PD program is money well spent – considering the way you do things on a shoe-string and the benefit your work has to the community.


  4. Hi Don: I was comparing investments in therapeutic stem cell-based therapies for Parkinson’s disease, not all funding, which includes basic research. Almost all of CIRMs funding for PD is for basic, not translational, research.

    Along with the European, Japanese, and New York projects, our project is poised to enter the clinic in 2019.

    We’ve done this with a tenth as much as the funding provided for this therapeutic plan by other agencies. We are disappointed in CIRM, but we are raising other funds to complete the work.

    There were discussions at the ICOC several years ago, when Joan Samuelson was on the board, about why CIRM wasn’t funding Parkinson’s disease therapeutic development…at that time, there was a feeling that there were no California researchers capable of doing this (I was at those ICOC meetings, so this is first-hand memory).

    But that was before my team turned to focus on Parkinson’s disease, and it’s time to have a fresh assessment of the capabilities of California researchers.

  5. Paul, I almost cry when I read of such cooperation. I hope that it can continue all the way through to having a more “public domain” approach to stem cell treatments that can benefit many. It is so uncommon. A couple of days ago I got a feed in my email from CSIRO
    Yep, most industries are certainly not about sharing. Given the long-out-of-date economic model to which most of us are forced to conform, this is sadly understandable.

  6. Interesting article, it’s encouraging that clinical trials are around the corner. But you were overly generous, 2.3 million out of 3 billion is less than 1/10 of 1 percent!

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