$2.5 million Defense Department grant funds gene therapy study for Lou Gehrig's disease

The Cedars-Sinai Regenerative Medicine Institute has received a $2.5 million grant from the Department of Defense to conduct animal studies that, if successful, could provide the basis for a clinical trial of a gene therapy product for patients with Lou Gehrig's disease, also called amyotrophic lateral sclerosis, or ALS.

The incurable disorder attacks muscle-controlling nerve cells – motor neurons – in the brain, brainstem and spinal cord. As the neurons die, the ability to initiate and control muscle movement is lost. Patients experience muscle weakness that steadily leads to paralysis; the disease usually is fatal within five years of diagnosis. Several genes have been identified in familial forms of ALS, but most cases are caused by a complex combination of unknown genetic and environmental factors, experts believe.

Because ALS affects a higher-than-expected percentage of military veterans, especially those returning from overseas duties, the Defense Department invests $7.5 million annually to search for causes and treatments. The Cedars-Sinai study, led by Clive Svendsen, PhD, professor and director of the Regenerative Medicine Institute at Cedars-Sinai Medical Center, and Geneviève Gowing, PhD, a senior scientist in his laboratory, also will involve a research team at the University of Wisconsin, Madison and a Netherlands-based biotechnology company, uniQure, that has extensive experience in human gene therapy research and development.

The research will be conducted in laboratory rats bred to model a genetic form of ALS. If successful, it could have implications for patients with other types of the disease and could translate into a gene therapy clinical trial for this devastating disease.

It centers on a protein, GDNF, that promotes the survival of neurons. In theory, transporting GDNF into the spinal cord could protect neurons and slow disease progression, but attempts so far have failed, largely because the protein does not readily penetrate into the spinal cord. Regenerative Medicine Institute scientists previously showed that spinal transplantation of stem cells that were engineered to produce GDNF increased motor neuron survival, but this had no functional benefit because it did not prevent nerve cell deterioration at a critical site, the "neuromuscular junction" – the point where nerve fibers connect with muscle fibers to stimulate muscle action.

Masatoshi Suzuki, PhD, DVM, assistant professor of comparative biosciences at the University of Wisconsin, Madison, who previously worked in the Svendsen Laboratory and remains a close collaborator, recently found that stem cells derived from human bone marrow and engineered to produce GDNF protected nerve cells, improved motor function and increased lifespan when transplanted into muscle groups of a rat model of ALS.

"It seems clear that GDNF has potent neuroprotective effects on motor neuron function when the protein is delivered at the level of the muscle, regardless of the delivery method. We think GDNF will be able to help maintain these connections in patients and thereby keep the motor neuron network functional," Suzuki said.

Svendsen's team now plans to directly deliver GDNF into muscle cells with AAV5, a "viral vector" – a virus stripped of its harmful genes and engineered to carry a beneficial gene into targeted cells. This will be supplied by uniQure, a biotechnology company that is collaborating with several research centers to conduct gene therapy clinical trials targeting other diseases.

In the new lab rat studies, AAV5 will be engineered to deliver GDNF into muscle tissue of the leg and the diaphragm, addressing two major aspects of ALS.

"The disease's effects typically start in one limb, beginning with weakness and leading to paralysis, before moving to other limbs and to muscles throughout the body. The most common cause of death is respiratory failure when the diaphragm muscles become incapacitated," said Svendsen, who has studied ALS for more than a decade and whose team will perform the leg muscle studies while Suzuki's group conducts the respiratory muscle experiments.

The Department of Defense grant will support all animal studies needed to take these experiments from the bench side to the bedside – leading to the filing of an Investigational New Drug application with the Food and Drug Administration. The IND process is a regulatory step between preclinical study and human clinical trials. If approved, Cedars-Sinai's large ALS Program, led by Robert H. Baloh, MD, PhD, has a clinical trials group in place to move this research into the clinic.

"Muscle is much more readily accessible for treatment and biopsy than brain tissue or the spinal cord, which makes this strategy very appealing," Svendsen said. "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 muscle may slow disease progression. We appreciate the Department of Defense's interest and funding, which will make it possible for us to further this exciting research."

Svendsen's research group in 2012 received a $17.8 million grant from the California Institute for Regenerative Medicine to develop stem cell treatments for patients with ALS based on injections of stem cells releasing GDNF into the spinal cord.

Provided by Cedars-Sinai Medical Center