Ceregene, Inc., a biopharmaceutical company, reported that its scientists and collaborators have published new experimental findings in support of its Parkinson’s disease programme 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 II b CERE-120 trial, was also reported. Raymond T. Bartus, PhD, 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 II study 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 II b clinical trial,” said Jeffrey M Ostrove PhD, 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 programme 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, MD, PhD, 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 I study in Parkinson’s patients, intended to provide initial evidence for the safety of this novel dosing paradigm.

Other authors of the paper include Christopher Herzog, Alistair Wilson, Lamar Brown and Joao Siffert (Ceregene, San Diego, CA), Y. Chu, Elliot Mufson and Jeffrey Kordower (Rush University Medical Center, Chicago, IL), Eugene Johnson, Jr. (Washington University, St Louis, MO) and C. Warren Olanow (Mt. Sinai School of Medicine, New York City).

CERE-120 is composed of an Adeno-Associated Virus (AAV) vector carrying the gene for neurturin, a naturally occurring protein known to repair damaged and dying dopamine-secreting neurons, keeping them alive and restoring normal function. Neurturin is a member of the same protein family as Glial cell-Derived Neurotrophic Factor (GDNF). The two molecules have similar pharmacological properties, and both have been shown to benefit the midbrain dopamine neurons that degenerate in Parkinson’s disease.

Degeneration of these neurons is responsible for the major motor impairments of Parkinson’s disease. CERE-120 has been delivered by stereotactic injection to the terminal fields (i.e., the ends of the degenerating neurons), located in an area of the brain called the putamen. The cell bodies for these same neurons are located in a different area of the brain, called the substantia nigra. Once CERE-120 is delivered to the brain, it provides stable, long-lasting expression of neurturin in a highly targeted fashion.

Ceregene has an ongoing phase I/II clinical trial of CERE-120 (AAV-neurturin) in patients with Parkinson’s disease. Enrollment in the phase II b portion of this clinical trial is active at 11 centres across the US. The goal of this clinical trial is to evaluate the safety and potential benefits of CERE-120 (AAV-neurturin) in the treatment of Parkinson's disease.

Parkinson's disease is a progressive movement disorder that affects a million people in the United States. Its main symptoms, stiffness, tremors and slowed movements and gait, are caused by a loss of dopamine-containing nerve cells in the substantia nigra, which project their axons to the putamen. Dopamine is a neurotransmitter involved in controlling movement and coordination, so Parkinson’s patients exhibit a progressive inability to initiate and control physical movements. There is currently no treatment that can reverse the degeneration of these neurons, let alone cure Parkinson’s disease.

Ceregene, Inc. is a San Diego-based biotechnology company focused on the delivery of nervous system growth (neurotrophic) factors for the treatment of neurodegenerative and retinal disorders using gene delivery, its clinical programmes include CERE-110, an AAV2 based vector expressing Nerve Growth Factor (NGF) currently in a multi-centre, controlled phase II study for the treatment of Alzheimer’s disease (in collaboration with the ADCS), and CERE-120 (AAV2-Neurturin) for Parkinson’s disease.