"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.
Mary Ann Schultz | EurekAlert!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences