Cedars-Sinai researchers are developing a novel way to treat amyotrophic lateral sclerosis (ALS) and retinitis pigmentosa using engineered stem cells that may eventually lead to personalized treatments.
The new approach uses cells derived from human induced pluripotent stem cells (iPSCs) that are renewable and scalable, and can also slow the progression of these neurodegenerative diseases in rodents.
This research, published in the journal Stem Cell Reportsmarks an important first step toward achieving more personalized therapies for people with these debilitating conditions for which there is currently no cure.
“In the past, we have had tremendous success using expanded populations of human brain tissue-derived neural progenitor cells combined with gene therapy to develop new treatments for ALS patients,” said Clive Svendsen, PhD, CEO of the Cedars-Sinai Board. of Government of the Institute of Regenerative Medicine and professor of Biomedical Sciences and Medicine.
The team previously showed that neural progenitor cells can be engineered to produce a protein called glial cell line-derived neurotrophic factor (GDNF), which helps keep neurons diseased.
This product was safely transplanted into the spinal cord of ALS patients in a recently completed trial. And after a single treatment, cells can survive and produce the critical GDNF protein for more than three years, thus potentially protecting dying motor neurons in ALS. These neural progenitor cells are also used in an ongoing trial for retinitis pigmentosa.
“However, the cell lines we use in the clinic come from a single source and will eventually run out. We just don’t have a never-ending product,” said Svendsen, who is also the Kerry Family Foundation and Simone Vickar Honoree. Chair of Regenerative Medicine at Cedars-Sinai. “Induced pluripotent stem cells provide a renewable source and allow us to develop a more sustainable product that can be engineered to release powerful growth factors.”
Scientists are finding cell and gene therapies that hold great promise in treating a variety of diseases, including difficult-to-treat neurodegenerative diseases such as ALS and retinitis pigmentosa. After the transplant, the stem cells generate support cells that release the drug designed to support the degenerating neurons. However, limitations that may hinder the widespread use and commercialization of these therapies include insufficient tissue availability and potential rejection of the cells by the patient.
“Being able to minimize immune interactions by engineering a patient’s own cells and then turning them into a precision medicine therapy has great potential,” said Alexander Laperle, PhD, project scientist in the Svendsen Laboratory and co-lead author. of the study.
To test the iPSC-based therapy, the team engineered iPSC-derived neural progenitor cells to produce GDNF, to see if it could be used to treat diseases that cause nervous system cell death, such as ALS and retinal degeneration.
The researchers found that placing these iPSC-derived neural progenitors into the eyes of rodents with retinal degeneration led to the protection of cells in the eye that support vision.
When the team transplanted the same cells into the spinal cord of rodents with ALS, they found that the cells helped protect cells in the spinal cord that control movement. They also found that these cells were safe and did not cause tumors or other problems when transplanted into the animals for several months.
“We saw that the cells survived and integrated into the spinal cord,” said co-author Alexandra Moser, PhD, a postdoctoral fellow in the Svendsen Lab. “They also largely formed astrocytes, which are supportive and protective cells, and we found that they continued to make GDNF. Most importantly, they did not form tumors.”
“We have successfully shown that we can develop human iPSCs that stably produce GDNF as a promising future cell and gene therapy,” Laperle said.
While the research results were promising, more preclinical studies are needed to determine the optimal treatment level, Moser noted. The team is currently looking at ways to improve the expansion of these cells and the scalability of that process.
The paper will also be part of a special edition of Stem Cell Reports on clinical translation of iPSC products, scheduled for publication in July 2023.
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