A Combined Cell and Gene Therapy Approach for Preserving Motor Neuron Function in ALS

December 21, 2022

Clive Svendsen, Ph.D., Cedars-Sinai Medical Center

Dr. Clive Svendsen
Dr. Clive Svendsen
(Photo Provided)

Amyotrophic Lateral Sclerosis (ALS) involves the progressive and often rapid death of motor neurons in the brain and spinal cord, as well as the loss of connections made by the spinal cord motor neurons to the muscle. Studies have shown that a powerful growth factor called glial cell-line derived neurotrophic factor (GDNF) can slow disease progression in models of ALS.

The lab of Dr. Clive Svendsen at Cedars-Sinai Medical Center utilizes a strategy to delay disease progression in ALS by delivering GDNF directly to motor neurons using a gene therapy approach. With support from a fiscal year 2013 Amyotrophic Lateral Sclerosis Research Program (ALSRP) Therapeutic Development Award (TDA), the Svendsen lab successfully delivered human neural progenitor cells secreting GDNF into the cortex of ALS models. Using this method, enhanced motor neuron function and extended survival was found, suggesting this approach confers protection of downstream motor neurons and may have positive effects on disease onset and patient lifespan.

In parallel, the Svendsen lab has been examining the safety of transplanting neural progenitor cells that have been engineered to produce GDNF into the spinal cord of ALS patients. After the transplantation, the 18 enrolled patients were observed for 1 year to monitor leg muscle strength. In a Nature Medicine publication released in September 2022, the results of the trial showed there were no negative effects of the cell transplant on leg muscle strength, and the phase 1/2a trial reached its primary endpoint of safety. This is the first study to show that allogeneic neural progenitors engineered to release GDNF can be safely transplanted into the human central nervous system. This proof-of-concept, showing a single delivery of genetically modified neural progenitor cells can sustain survival and release of a protein product, represents a novel therapeutic option for ALS and other neurodegenerative diseases. and combined with the data from the ALSRP study, has now allowed the team to use the same cells in a clinical trial focusing on delivery to the upper motor neurons.

Regarding the early support from the ALSRP, Dr. Svedsen said, “The support from ALSRP allowed us to do all of the small and large animal pre-clinical studies required to move to a new patient trial currently underway. ALS is a very tough disease to treat, and this research gives us hope that we are getting closer to finding ways to slow down this disease.”

Treating multiple sites, using this approach, may further enhance clinically meaningful effects, and this therapeutic approach is now being considered for the cervical spinal cord and motor cortex, two regions showing benefit from these cells in ALS models. Given encouraging outcomes from this initial trial, a combined cell and gene therapy approach holds great promise for patients with this relentless disease that has no effective treatment.


Public and Technical Abstracts: Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS

Progenitor Cells Secreting GDNF for the Treatment of ALS

CNS10-NPC-GDNF for the Treatment of ALS

Stem Cell-Gene Therapy Shows Promise in ALS Safety Trial

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial

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Last updated Monday, December 19, 2022