First evidence of neurotrophic factors improving status of degenerating dopamine neurons in Parkinson's brains

Ceregene, Inc., a biopharmaceutical company, reported today that its scientists and collaborators have published new experimental findings in support of its Parkinson's disease program which appeared as the lead article in the current issue of Movement Disorders (the official journal of the Movement Disorders Society).  The publication reports the first evidence that gene transfer can provide targeted expression of a neurotrophic factor, i.e., neurturin or NRTN, intended to restore and preserve dying neurons.  Moreover, it provides the first evidence that neurotrophic factors can improve the status of degenerating dopamine neurons in Parkinson's brains.  New insight important for further improving the bioactivity of NRTN in advanced Parkinson's disease, implemented in the current Phase 2b CERE-120 trial, was also reported.  Raymond T. Bartus, Ph.D., Ceregene's executive vice president and chief scientific officer, who has led the development of CERE-120, is the lead author of the publication.

CERE-120, Ceregene's neurotrophic therapy, currently being clinically tested in advanced Parkinson's disease (PD), is partially funded by the Michael J. Fox Foundation for Parkinson's Research.  CERE-120 is comprised of a viral vector intended to provide constant, sustained expression of neurturin, a neurotrophic factor shown to rescue dying dopaminergic neurons, restoring their function and protecting them from death.  The data in this publication were derived from an analysis of autopsied brain tissue from two patients who were treated in a previous CERE-120 Phase 2 study (see Ceregene press release, May, 2009) and later died of causes unrelated to the treatment.  Ceregene has since confirmed and extended these results by showing persistent, targeted NRTN expression in a patient who had been treated with CERE-120 five years earlier.  

"This new publication provides a strong scientific rationale for our overall clinical strategy for Parkinson's disease, as well as for the modified dosing paradigm we are employing in our ongoing Phase 2b clinical trial," said Jeffrey M. Ostrove Ph.D., president & chief executive officer of Ceregene.  "We very much appreciate the unselfish courage of patients and the immediate family of patients who volunteer to participate in experimental clinical trials and agree to donate their organs for scientific study after their death.  The information we gained from the brains of two of our study participants was instrumental in significantly improving our understanding of NRTN expression in the PD brain, which then allowed us to enhance our dosing paradigm and continue to move this program forward with confidence of ultimate success."

The paper, entitled "Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences between Parkinson's Disease and Nonhuman Primate Brains," was further highlighted by a guest editorial commenting on several important elements of the paper.  Additionally, brain images of NRTN expression following CERE-120 treatment in Parkinson's patients were prominently displayed on the front cover of the issue.  The guest editorial (written by Travis Lewis and David Standaert, M.D., Ph.D., University of Alabama, Birmingham) called the paper a "milestone in the development and refinement of neurotrophic factor gene therapy," providing "proof that gene therapy with AAV2-NRTN (aka CERE-120) results in functional...transgene expression in target cells in humans."  The guest editors further opined that "as one of the few therapies immediately available that may not only slow PD expression, but also improve outcomes, we feel that the potential benefits of a clinically successful CERE-120 treatment cannot be ignored."  

Other key findings in the paper resulted from comparing and contrasting the pattern of NRTN expression and bioactivity seen in the Parkinson's brains versus that seen in nonhuman primates, including contemporary models of Parkinson's disease.  In Parkinson's brains and in nonhuman primate brains, CERE-120 resulted in comparable NRTN expression in the targeted putamen, where the degenerating nerve terminals reside. However, in the case of Parkinson's disease, very little NRTN was seen in the cell bodies of the same degenerating neurons, which are located in a different brain region, called the substantia nigra.

Dr. Bartus stated, "These data warned us of a fundamental deficiency in Parkinson's disease brains which limits how effectively NRTN is transported from the terminals of degenerating neurons to their cell bodies.  This provided the key insight we needed to appreciate the need to directly inject CERE-120 into the substantia nigra (thus reducing dependency on retrograde transport), in addition to injecting a larger dose into the putamen.  These dosing changes are intended to help assure that the entire degenerating neuron is exposed to sufficient neurotrophic factor, assuring that a more robust neurotrophic response is stimulated, in turn, further enhancing and accelerating neuronal repair."  In June 2010, Ceregene announced that it had successfully completed a new Phase 1 study in Parkinson's patients, intended to provide initial evidence for the safety of this novel dosing paradigm.