Wednesday, June 20, 2018

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. 

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  1. Interesting article, David! The second link you gave at the end of the article isn't accessible. Could you please fix that?

  2. My apologies for bungling the link. It has been fixed. Thanks.