Long Island researchers: Gene therapy helps with Parkinson's

An experimental form of gene therapy designed to treat Parkinson's disease apparently causes the brain to "rewire" itself and improves patients' ability to move more fluidly , a team of Long Island researchers has found. 

The gene therapy is expected to proceed into a Phase 3 clinical trial next year, according to lead investigator Dr. David Eidelberg of the Feinstein Institute for Medical Research in Manhasset. A Phase 3 trial involves randomized testing in a large group of patients, in which some will receive gene therapy and others a so-called sham, or placebo, procedure.

The trial will not be double-blind, as occurs in drug studies, because doctors will know which patients are receiving new genes and which undergo the procedure that serves as the placebo. 

Parkinson's dramatically affects motor activity and is characterized by a loss of cells that produce the vital chemical dopamine. The incurable disorder is the second most common neurodegenerative disease in the United States after Alzheimer's, affecting 1 in every 100 people over age 60.

Eidelberg and his collaborators have analyzed several years' worth of research on the treatment and have found that the infusion of new genes directly into the brain causes novel circuits to develop, resulting in improvements in movement. 

"What we found were powerful effects, not just at the site where the genes were injected, but way downstream [in the brain] there was a complete reorganization into this unique circuit," Eidelberg said.

The treatment appears to be most effective in eliminating slowness and stiffness — two key problems affecting people with Parkinson's. The condition additionally is marked by muscle rigidity, tremors and changes in speech and gait.

Eidelberg said there was a surprising yet potent effect among patients who thought they had received new genes, but actually were in the sham portion of the research and did not receive the treatment. To a lesser extent, they, too, developed new brain circuits that improved their ability to move, which he attributed to the power of positive thinking and the belief that they had received new genes.

In a statement, Dr. Kevin Tracey, president and chief executive of the Feinstein Institute, said Eidelberg's work has written a new chapter on understanding the brain under assault by the disorder.

The research "has opened important new avenues for mapping brain networks that are fundamental to understanding debilitating movement disorders,” Tracey said.

Gene therapy involves the infusion of DNA into affected cells to correct serious medical disorders. In recent years, various forms of the treatment have been approved by the U.S. Food and Drug Administration.

Last December, the FDA approved a gene therapy procedure to treat an inherited form of blindness called Leber's congenital amaurosis. Up to 1 billion genes are injected directly into the eyes of Leber's patients.

In December 2016, the agency approved another form of gene therapy codeveloped by Dr. Adrian Krainer of Cold Spring Harbor Laboratory. That treatment addresses spinal muscular atrophy, or SMA, in young children, a once-deadly condition that affects the central nervous system, robbing children of their ability to walk, eat and breathe.

Parkinson's is a condition that causes a range of symptoms and is more complex to treat through gene therapy than disorders known as single-gene defects, Eidelberg said, referring to disorders that have only one gene that is missing or mutated.

"Most people have no family history of Parkinson's disease," he said, "so it is not like muscular dystrophy or retinal blindness, where you need to get one gene in place. Parkinson's is a very difficult disease to assault strategically, but the results, so far, are promising."

Reporting Wednesday in Science Translational Medicine, Eidelberg and his team explained the underlying mechanisms involving their gene therapy, which is dubbed AAV2-GAD. The treatment entailed delivering a gene that carries the code for the enzyme glutamic acid decarboxylase, or GAD. New genes help stimulate the non-dopamine brain cells to produce that chemical and improve movement and relieve stiffness.

"We found that AAV2-GAD leads to the formation of new neural pathways in the brain, connecting the subthalamic nucleus to other motor regions, thereby improving motor symptoms for as long as 12 months," Eidelberg said.