Engineering the next generation of cell and gene therapies

The new approach uses cells derived from human induced pluripotent stem cells (iPSCs) that are renewable and scalable, and also can delay the progression of these neurodegenerative diseases in rodents.

This research, published in the journal Stem Cell Reports, marks an important first step toward achieving more personalized therapies for people with these debilitating conditions that currently have no cures.

"In the past, we have had an enormous success using expanded populations of neural progenitor cells derived from human brain tissue combined with gene therapy in developing new treatments for patients with ALS," said Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute 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 sustain diseased neurons.

This product was safely transplanted in the spinal cord of patients with ALS in a recently completed trial. And after a one-time treatment, the cells can survive and produce the critical GDNF protein for over three years, thereby potentially protecting motor neurons that die in ALS. These neural progenitor cells are also used in an ongoing trial for retinitis pigmentosa.

"However, the cell lines we are using in the clinic are coming from a single source and are going to eventually run out. We just don't have endless product," said Svendsen, who is also the Kerry and Simone Vickar Family Foundation Distinguished Chair in 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 to hold great promise in treating a variety of diseases, including hard-to-treat neurodegenerative diseases like ALS and retinitis pigmentosa. After transplantation, stem cells generate support cells that release the engineered drug to provide support to degenerating neurons. Yet limitations that can hinder 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 that into a precision medicine therapy has very strong potential," said Alexander Laperle, PhD, a project scientist in the Svendsen Laboratory and co-first 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 cells to die, such as ALS and retinal degeneration.

The investigators found that putting these iPSC-derived neural progenitors into the eyes of rodents with retinal degeneration led to protection of the cells in the eye that support vision.

When the team transplanted the same cells into the spinal cords of rodents with ALS, they found the cells helped protect the spinal cord cells 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-first author Alexandra Moser, PhD, a postdoctoral fellow in the Svendsen Laboratory. "They also largely formed astrocytes, which are protective and supportive cells, and we found they continued to produce GDNF. Most importantly, they didn't form tumors."

"We have successfully shown that we can develop human iPSCs that stably produce GDNF as a promising future cell and gene therapy," said Laperle.

While the research results showed promise, more preclinical studies are needed to determine the optimal treatment level, noted Moser. 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 issue of Stem Cell Reports on clinical translation of iPSC products, which is scheduled to publish in July 2023.