Scientists Find Key to Control Neural Protein
Cedars-Sinai stem cell scientists have shown they can manipulate the production of a neural protein—critical to survival of motor neurons—by specially engineered cells. Their achievement is an important step in refining investigative therapies for amyotrophic lateral sclerosis (ALS), Parkinson's disease and other neurodegenerative disorders.
The protein, glial cell line derived neurotrophic factor (GDNF), supports glial cells, which help keep alive the motor neurons that control muscle movement. In ALS patients, these motor neurons die, causing progressive paralysis and ultimately death. There is growing evidence that GDNF is linked with protection of motor neurons and amelioration of ALS.
More than 12,000 people in the U.S. have ALS, commonly known as Lou Gehrig's disease, according to the National Institutes of Health (NIH). Although drugs and mechanical devices can help alleviate symptoms, there is no effective treatment, and most patients die within five years.
In the study, published June 5 in Stem Cell Reports, investigators harnessed a common antibiotic, doxycycline, to both stop and start production of GDNF by neural progenitor cells that had been genetically reprogrammed to produce GDNF. This ability, demonstrated in animal models, improves the potential usefulness of the combined gene and stem cell strategy in experimental treatments for a range of disorders, they said.
"This report provides proof-of-concept that GDNF produced by engineered human neural progenitor cells can be tightly regulated across multiple cycles in vivo," said Joshua Breunig, PhD, assistant professor of Biomedical Sciences and a research scientist at the Cedars-Sinai Board of Governors Regenerative Medicine Institute. "This technology can be applied to other growth factors, providing a valuable means to protect neurons damaged in different diseases."
Specifically, GDNF administration could be reduced or stopped if patients were to develop side effects or desensitization during treatment, or it could be varied to allow for resensitization, explained Breunig, a co-corresponding author of the study. These options could be especially valuable in Parkinson's disease, a neurodegenerative disorder that progresses more slowly than ALS and also may benefit from GDNF administration, he added. More than 1 million people in North America have Parkinson's, according to the NIH.
The research team noted that translating their experimental therapy to the clinic would require more safety and efficacy testing. As a next step, using animal models, they are investigating how the engineered neural progenitor cells might migrate into areas of brain damage and whether it is possible to target larger regions of the brain.
"Cedars-Sinai researchers are committed to opening multiple fronts in their drive to develop treatments to attack ALS and other neurodegenerative disorders," said Clive Svendsen, PhD, professor of Biomedical Sciences and Medicine and director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute. Svendsen was a co-corresponding author, along with Breunig, of the Stem Cell Reports study. Aslam Abbasi Akhtar, PhD, was the first author.
Previous Cedars-Sinai research, published in the journal Stem Cells, demonstrated that by transplanting GDNF-secreting neural progenitor cells into the brain cortices of laboratory rats, progression of ALS was delayed and survival was extended. GDNF also is key to an ongoing Cedars-Sinai clinical trial that involves transplanting GDNF-producing stem cells into the spinal cords of ALS patients, with the goal of preserving motor neurons and improving leg mobility.
Funding: Research reported in this publication was supported by the National Institutes of Health under award number R33-CA202900, the American Cancer Society, the Cedars-Sinai Board of Governors Regenerative Medicine Institute and the California Institute for Regenerative Medicine.