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.
“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 4 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, Ph.D., Sr. 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.
