Ceregene announces its own promising gene therapy trial for PD patients.

HD Lighthouse Contributing Editor's Comment: The results of a Phase I trial of gene therapy in Parkingon's Disease were announced by Ceregene last week and they also look promising. In this study, patients received a gene for a growth factor called neurturin which is thought to be neuroprotective. An adeno-associated viral (AAV) vector was used to deliver the gene. Patients who received a lower dosage experienced a 40 percent reduction in Parkinson's symptoms and those who received a higher dosage experienced a 50 percent reduction. They have been followed for nine months.

Ceregene is also researching gene therapy for Huntington's Disease. The preclinical results with a mouse model look promising. Glial-derived neurotrophic factor (GDNF) was used rather than neurturin; GDNF is similar. To read more about neurotrophic factors, go here: Neurotrophins to the rescue

The press releases for the PD and HD studies can be found below along with the abstract of an academic article about the HD study.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 20 Oct 2006

Ceregene Announces Promising Phase I Results from Gene Therapy Trial for Parkinson's Disease

Michael J. Fox Foundation Awards $1.9 Million for Phase 2 Efficacy Study

San Diego, CA, October 10, 2006 – Ceregene, Inc., announced today that CERE-120, a gene therapy product in development for the treatment of Parkinson’s disease, was well tolerated and appeared to reduce symptoms by approximately 40% (p<0.001), as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) motor “off” score, in an open-label Phase 1 study in 12 patients with advanced disease. Initial results of the study were presented by William J. Marks Jr., M.D., principal investigator of the study and associate professor of Neurology at the University of California, San Francisco (UCSF) today at the American Neurological Association annual meeting in Chicago.

The study was supported in part by a grant from The Michael J. Fox Foundation for Parkinson’s Research. Based on the initial results, the Foundation today announced plans to partially fund a Phase 2 study with a $1.9 million grant

“We were encouraged by the results of the Phase 1 trial,” said Deborah W. Brooks, president and CEO of The Michael J. Fox Foundation. “Based on these and on the intriguing efficacy observations, we’re eager to continue to support research in Phase 2 that will more definitively assess the potential of CERE-120 to treat PD.”

CERE-120 is comprised of an adeno-associated virus (AAV) vector carrying the gene for neurturin (NTN), a naturally occurring protein, whose role is to keep dopamine-secreting neurons alive and functioning normally. All 12 patients enrolled in the study underwent stereotactic neurosurgery to deposit CERE-120 into their putamen. The putamen is a region of the brain that undergoes degeneration and reduced dopamine production in Parkinson’s disease patients and this has been closely linked to the major motor deficits in these patients. All patients entered in the trial were judged to have inadequate control of their disease with standard levodopa therapy and were otherwise potential candidates for additional treatment interventions such as deep brain stimulation (DBS) surgery.

CERE-120 was delivered at 2 different doses, with patients receiving the low dose demonstrating approximately 40% improvement in UPDRS motor “off” scores by 9 months and patients receiving the 4-fold higher dose showing a similar effect 3 months sooner. Patients also demonstrated a 50% reduction in hours of “off” time (i.e., time when normal Parkinson’s medication was ineffective and symptoms were troubling to the patient) and a doubling of good quality “on” time without dyskinesias (i.e., time when a patient is functioning well) according to self-reported diaries.

NTN (neurturin) is a member of the same protein family as glial cell-derived neurotrophic factor (GDNF) and the two molecules have similar pharmacological properties. GDNF has previously been tested in Parkinson's disease patients. Ceregene owns exclusive technology and product rights to CERE-120.

“Targeted delivery of the trophic factor neurturin is a compelling approach to treating Parkinson's disease,” said Dr. Marks. “The safety data and preliminary efficacy data that we have seen in this Phase 1 study are encouraging. Clearly, a larger-scale study is warranted.”

According to Dr. Marks, existing treatments for Parkinson's disease treat symptoms only, and for only a limited period of time. “Patients with Parkinson's disease urgently need therapeutic approaches that not only improve symptoms and function, but also have the ability to modify the underlying disease itself in a favorable manner,” he said.

In addition to Dr. Marks, the study was authored by: Jill Ostrem, M.D., UCSF neurologist; Philip Starr, M.D., Ph.D. and Paul Larson, M.D., who conducted the neurosurgery at UCSF; neurologist Leo Verhagen, M.D. with neurosurgeon Roy Bakay, M.D. at Rush University Medical Center in Chicago; and Raymond T. Bartus, Ph.D., who led the clinical and preclinical development of CERE-120 at Ceregene.

“The planned Phase 2 trial will be a randomized controlled trial involving approximately 50 patients, and is designed to test if the efficacy we have seen in our initial Phase 1 trial will hold up in a controlled study,” stated Jeffrey M. Ostrove, Ph.D., president and CEO of Ceregene.

06/13/06

Gene Therapy Injected into the Brains' of Mice with Huntington's Disease Protects Neurons, Stop Degeneration and Improves Behavioral Function

Researchers at Rush University Medical Center, Chicago, and Ceregene Inc. San Diego have successfully used gene therapy to preserve motor function and stop the anatomic, cellular changes that occur in the brains of mice with Huntington's disease (HD). This is the first study to demonstrate that, using this delivery method, symptom onset might be prevented in HD mice with this treatment. Results of the study were published in the Proceedings of the National Academy of Sciences of the United States, June 13.

"This could be an important step toward a disease modifying therapy," says co-author Jeffrey H. Kordower, Ph.D., director of the Research Center for Brain Repair at Rush. "We could potentially be stopping the disease process in its tracks, delaying symptoms from ever showing up."

Huntington's disease is an inherited degenerative disease that progressively robs patients of the ability to think, judge appropriately, control their emotions and perform coordinated tasks. HD typically begins in mid-life, between the ages of 40 and 50. There is no effective treatment or cure for this fatal illness that affects 30,000 Americans and places another 75,000 at risk.

Kordower says this research, if eventually applied to humans, could help those who have HD or, due to the presence of a genetic test, are known to be destined to get HD.

"Each child of an affected parent has a 50 percent risk for inheriting the disease. Genetic testing can identify mutated gene carriers destined to suffer from HD. Unlike other neurodegenerative disorders, identification of the genetic markers provides a unique opportunity to intercede therapeutically before or extremely early in the disease process-only a small fraction of potential carriers get tested. But, if there was a treatment, especially one that altered the natural course of disease, potentially halting it, we would hope every potential patient would get tested so they could avail themselves to the therapy."

Researchers used a defective virus, adenoassociated viral vector, (AAV) to deliver gene therapy (glial-derived neurotrophic factor (GDNF) directly to the brain cells of mice.

GDNF is one of two closely related, naturally-occurring nutrients that strengthen and protect brain cells that would normally die in this disease. The other neural nutrient is called neurturin (NTN). GDNF and NTN also increase production of the chemical neurotransmitter dopamine, which sends signals in the brain that enable people to move smoothly and normally. Ceregene, Inc, whose scientists co-authored this paper, is developing AAV-NTN (called CERE-120) as a potential treatment for several neurodegenerative diseases, while using AAV-GDNF for 'proof of principle' research studies.

The mice in this study were injected with the gene for GDNF encased in a harmless viral coating, which protects the gene and facilitates its delivery to brain cells. The virus coating (AAV vector) that carries the gene is well studied and has been used in several other gene transfer studies to deliver different genes for Parkinson's disease and Alzheimer's disease patients. The vector is no longer a true virus as it cannot replicate on its own and no longer contains any of its own genes. The vector has been engineered to transfer the gene for the brain nutrient selectively to the area of the brain where it is needed to protect the degenerating cells.

Three groups of mice were involved in the four month study. All mice were modeled to have the genetics of HD. The HD mice exhibited symptoms of motor deficits including loss of control, gait abnormalities, hypokinesia (abnormally decreased mobility and motor function), hind limb clasping behaviors and muscle weakness. One control group of mice did not receive any gene therapy. A second control group was injected with a placebo gene therapy. The third group received the active GDNF gene therapy.

To measure fine motor coordination, balance and fatigue, researchers evaluated mice walking on a rotating rod. Mice injected with the gene therapy performed significantly better than the other mice. These mice also showed diminished hind limb clasping, (a simulation of motor control behavior in HD patients). Perhaps most importantly, gene delivery of GDNF provided neuroprotection in the brain, with reduced density of brain inclusions and less cell death.

The authors wrote "Although GDNF's exact role in preventing cell death in mice modeled with HD remains to be established, we speculate the increase trophic support and inhibiting apoptosis (programmed cell death) via these two pathways likely played integral roles."

Kordower says the study suggests a new approach to forestall disease progression in newly diagnosed HD patients by delivering potent trophic factors with effects that are long-term and non-toxic." "If these results can be replicated in HD patients, it would represent a significant advance in the treatment of this tragic disease", agreed Dr. Jeffrey Ostrove, President and CEO of Ceregene.

"We are pleased with the results of this 'proof of concept' study with AAV-GDNF in HD mice", stated Raymond T. Bartus, PhD, senior vice president, Clinical and Preclinical R&D and COO, Ceregene. "We now look forward to completing ongoing studies with our product, AAV-NTN (CERE-120), in HD mice, also performed in collaboration with Dr. Kordower and Rush University Medical Center," Bartus added.

Ceregene's lead program with CERE-120 is in Parkinson's disease (PD). The company completed enrollment of a Phase I trial with CERE-120 at UCSF and Rush University Medical Center, which was reported to be safe and well tolerated in PD patients at the American Association of Neurology meeting last spring. Initial efficacy results of this Phase I trial are expected to be presented this fall and a double-blinded, controlled Phase II trail in PD patients is planned for later this year.

The research was supported by grants from the National Institutes of Health, including the SBIR program, The Shapiro Foundation, The Consolidated Anti-Aging Foundation, and Ceregene Inc.

Journal Abstract

JL McBride, S Ramaswamy, M Gasmi, RT Bartus, CD Herzog, EP Brandon, MR Pitzer, L Zhou, EM Berry-Kravis, JH Kordower. Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington's disease. Proceedings of the National Academy of Sciences of the United States of America 2006 Jun 13;103(24):9345-50.

Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.

Source: Press Release

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