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Andrew Klein
ank2017@med.cornell.edu

How NLX-P101 Gene Therapy Works

Gene therapy is the use of a gene to change the function of cells or organs to improve or prevent disease. To transfer genes into cells, an inert virus is used to deliver the gene into a target cell. In this case, the glutamic acid decarboxylase (GAD) gene was used because GAD makes a chemical called GABA, a major inhibitory neurotransmitter in the brain that helps "quiet" excessive neuronal firing related to Parkinson's disease.

"In Parkinson's disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement," explains Dr. During.

In the Phase 2 study, each patient in the experimental group received an infusion of the genetic material directly into their subthalamic nucleus, a key brain region involved in motor function. The GAD gene instructed cells in that area to begin making GABA neurotransmitters in order to re-establish the normal chemical balance which becomes dysfunctional within circuits that control movement.

While patients in the Phase 1 study only received the therapy on one side of their brain, patients in the Phase 2 were infused on both sides. And while the infusion happened entirely in the operating room in the previous phase, the current study made use of a novel delivery system conceived by Drs. Kaplitt and During that allowed for the infusion to take place outside of the OR — at the hospital bedside — something Dr. Kaplitt says makes for a more comfortable patient experience.

Drs. Kaplitt and During also designed the sham surgery, one of the most complex of its kind. The challenge was especially great because patients were required to remain awake to enable surgeons to locate the targeted brain area. In the sham procedure, a small indentation was drilled partway into their skull. Pre-recorded audio of a subthalamic nucleus mapping procedure was played while patients were asked to move various body parts, leading them to believe that an actual brain procedure was being performed. Lastly patients were attached to an infusion system that appeared identical to the system used in the gene therapy group but were subcutaneously injected with saline solution instead of the gene therapy.

The NLX-P101 gene therapy was pioneered by Neurologix Inc. scientific founders Drs. Kaplitt and During. The two researchers have been at the forefront of gene therapy research since 1989. They were the first to demonstrate that the viral vector AAV could be an effective gene therapy agent in the brain, which they reported in a landmark Nature Genetics paper in 1994. Drs. During, Kaplitt and colleagues subsequently published additional research demonstrating the beneficial effects of AAV-GAD gene therapy for Parkinson's in the journal Science in 2002. The Phase 1 clinical trial, performed at NewYork-Presbyterian/Weill Cornell, was the first ever clinical gene therapy trial for Parkinson's or any other adult neurological disorder. Results of that study appeared in 2007 as a cover article in The Lancet and in a second article in the Proceedings of the National Academy of Sciences.

The Phase 2 study was funded by Neurologix Inc., of Fort Lee, N.J., which is developing the adeno-associated virus-borne GAD (AAV-GAD) agent and has licensed intellectual property rights to NLX-P101 gene therapy. Drs. Kaplitt and During are co-founders of the company and remain paid consultants. Additionally, Dr. Kaplitt's father, Dr. Martin Kaplitt, is chairman of the board of Neurologix, and as such has stock ownership and receives salary.
Leading the study were neurologists Dr. Andrew Feigin of the North Shore — LIJ Health System in Manhasset, N.Y., and Dr. Peter A. LeWitt of the Henry Ford Health System in West Bloomfield, Mich.

Additional co-authors include Jason M. Schwalb from the Henry Ford Health System, West Bloomfield Charter Township, Mich; Ali R. Rezai, Sandra K. Kostyk, Karen Thomas and Atom Sarkar from the Ohio State University College of Medicine, Columbus, Ohio; Maureen A. Leehey and Steven G. Ojemann from the University of Colorado School of Medicine, Aurora, Colo.; Alice W. Flaherty and Emad N. Eskandar from the Massachusetts General Hospital, Boston; Mustafa S. Siddiqui and Stephen B. Tatter from the Wake Forest University School of Medicine, Winston-Salem, N.C.; Kathleen L. Poston and Jaimie M. Henderson from the Stanford University School of Medicine, Stanford, Calif.; Roger M. Kurlan and Irene H. Richard from the University of Rochester School of Medicine, Rochester, N.Y.; Lori Van Meter from PharmaNet Development Group, Princeton, N.J.; and Christine V. Sapan from Neurologix Inc., Fort Lee, N.J.

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