The Department of Defense recently provided a grant to the Cedars-Sinai Regenerative Medical Institute to fund animal studies that may help pave the way to a clinical trial of a gene therapy product for patients with amyotrophic lateral sclerosis (ALS). A news release from Cedars-Sinai Medical Center states that study leaders include Clive Svendsen, PhD, professor and director of the Regenerative Medicine Institute at Cedars-Sinai Medical Center, and Geneviève Gowing, PhD, senior scientist in Svendsen’s lab. The study will also involve a research team at the University of Wisconsin, Madison and a Netherlands-based biotechnology company, uniQure.

The study encompasses a protein GDNF, which reportedly promotes the survival of neurons. The release notes that transporting GDNF into the spinal cord is intended to protect neurons and slow disease progression, however, to date, attempts have failed primarily because the protein does not readily penetrate into the spinal cord. Prior research conducted by Regenerative Medicine Institute scientists previously indicated that spinal transplantation of stem cells designed to produce GDNF increased motor neuron survival, but showed no functional benefit as it did not prevent nerve cell deterioration at a critical site, the “neuromuscular junction.”

Masatoshi Suzuki, PhD, DVM, assistant professor of comparative biosciences, University of Wisconsin, Madison, is a close collaborator in the research, according to the release. Suzuki recently discovered that stem cells derived from human bone marrow and engineered to produce GDNF protected nerve cells, improved motor function. It also increased lifespan when transplanted into muscle groups of a rat model of ALS, the release states.

Suzuki says that it appears to be clear that the protein has neuroprotective effects on motor function when the protein is delivered at the level of the muscle, regardless of delivery method.  “We think GDNF will be able to help maintain these connections in patients and thereby keep the motor neuron network functional,” Suzuki adds.

In the current research, Svendsen’s team plans to directly deliver GDNF into muscle cells with AAV5, a “viral vector,” the release notes. The viral vector will be supplied by uniQure. In the lab rat studies, AAV5 will be designed to deliver GDNF into muscle tissue of the leg and the diaphragm, addressing two major aspects of ALS.

Svendsen points out that ALS’ effects typically present in one limb, beginning with weakness and leading to paralysis, before moving to other limbs and muscles throughout the body. “The most common cause of death is respiratory failure when the diaphragm muscles become incapacitated” Svendsen says.

The release reports that the $2.5 million grant will support all animal studies required to take the experiments from bench side to bedside, eventually paving the way to the filing of an Investigational New Drug application with the FDA. Should the application be approved, the release says Cedars-Sinai’s large ALS Program, led by Robert H. Baloh, MD, PhD, has a clinical trials group in place to move the research into the clinic.

“Our previous findings provide strong evidence that the viral vector can transfer the GDNF protein into muscle, and we have shown that GDNF delivered to muscles may slow disease progression. We appreciate the Department of Defense’s interest and funding, which will make it possible further exciting research,” Svendsen emphasizes.

Source: Cedars-Sinai Medical Center