Society for Neuroscience: Viral Vectors for Huntington’s and Parkinson’s Disease
Speakers: Anders Bjorklund, MD, University of Lund, Sweden; Beverly Davidson, PhD, University of Iowa; Nicole Deglon, PhD, Atomic Energy Commission, Orsay, France; Patrick Aebischer, MD, Ecole Polytechnique Federale de Lausanne, Switzerland; and Deniz Kirik, MD, PhD, University of Lund, Sweden
Techniques using stripped-down altered viruses (viral vectors) create improved animal models of disease and hold promise for patients with serious neurological ailments.
The viral vector technique relies on the ability of viruses to invade cells and transfer genetic material. Whereas a cold virus would transfer cold-producing genetic material, the stripped-down viruses are altered to transfer genetic material that can reproduce the effects of a certain neurological disease in an animal model. Alternatively, in the case of drug therapy, they can transfer genetic material that can stop the biological mechanisms that underlie a neurological disease.
buy antibiotics canada
Our genes produce proteins that control brain development and function. In Huntington’s disease (HD), however, a faulty version of a gene, termed “huntingtin,” produces a flawed protein that causes the system to go awry. As a result, people with the faulty gene experience cell damage and destruction in the brain’s basal ganglia and cortex. This can affect coordination, thought, perception, and memory. Many patients experience involuntary movements of the arms, legs, body, and face. These symptoms are often accompanied by mood swings, depression, irritability, slurred speech, and clumsiness.
As the disease progresses, patients can have difficulty swallowing and can experience loss of balance, impaired reasoning, and memory problems. Death is commonly caused by a complication of the disease such as choking, or an injury related to a fall.
“Therapies for HD are often targeted at reducing the toxic effects or other properties of the flawed huntingtin protein,” says Beverly Davidson, PhD.
Dr. Davidson and her colleagues used a viral vector to deliver small fragments of genetic material to suppress the production of the flawed huntingtin protein.
“Our use of this technique, also known as RNA interference, is the first example of targeting the fundamental underlying problem in HD,” she says. “If we can get rid of the flawed protein, we should have a great impact on the disease.”
buy antibiotics without prescription
In the study, the technique reduced flawed huntingtin levels to 40% of pretreatment levels. In addition, the technique reduced clumps in cells. These clumps are normally formed by the flawed huntingtin protein. The reduction in protein levels correlated with improvements in movement problems seen in mice with HD, such as wavering when they walked or an inability to keep their balance on a rotating rod.
“The data suggest that even slowing down, rather than completely stopping, the production of the flawed protein can give the cells a chance to catch up and clear up the problems caused by mutant huntingtin,” Dr. Davidson explains.
The mouse model used by the researchers demonstrated disease symptoms very early on.
The researchers plan to test the therapy in a model that more closely resembles human HD in which the symptoms are more subtle and take many more months to appear. Other researchers have developed improved animal models with the aid of viral vector techniques.
Most recently, other researchers used a viral vector technique to create a non-human primate model of HD. First, they found that a viral technique, used in adult rats, boosted production of the flawed huntingtin protein in the brain area known to be affected by HD resulted in a selective and severe neuropathology characterized by huntingtin clumps in cells, brain cell dysfunction, and the cell death typical of HD. Non-human primates injected with the viral vector also showed behavioral deficits associated with HD.
buy levitra uk
In parallel with these studies, the researchers are also testing the use of viral vectors to treat pathological states. For example, they are developing a viral vector-based RNA interference technique, similar to Dr. Davidson’s, that may block or delay the appearance of HD symptoms. Other researchers have used viral vectors to create animal models of Parkinson’s disease (PD), which helped them identify ways to treat the movement disorder.
PD is characterized by slow movements, tremors, muscle rigidity, and gait and postural deficits. These symptoms are the consequence of the specific degeneration of brain cells that secrete the chemical dopamine in the substantia nigra brain area, which is involved in the control of voluntary and involuntary movements.
The pathological hallmark of PD is the presence of clumps in degenerating brain cells, called Lewy bodies. Several mutated genes have been linked to forms of PD, including two that affect a protein called alpha-synuclein.
“Although these mutations account for only rare cases of Parkinson’s disease, alpha-synuclein is also one of the primary components of the Lewy bodies, the pathological hallmark of PD, supporting a central role for alpha-synuclein in all forms of PD,” says Patrick Aebischer.
In a new study, Dr. Aebischer and his colleagues developed an animal model of PD that targets alpha-synuclein with viral vector approaches. Researchers injected mutated forms of the alpha-synuclein gene into rats in the brain region that is affected in the human disorder.
suhagra 100
“By doing this, we developed a genetic model of PD that recreated the major pathological features of the disease such as the specific death of the dopamine-secreting brain cells in the substantia nigra brain area and the presence of intracellular clumps resembling Lewy bodies in the human disease,” says Dr. Aebischer. “These results were confirmed by the successful development of a similar PD model using another virus as gene carrier in both rats and non-human primates.”
In a second part of the work, researchers determined through studies of these animal models that increasing the expression of a gene termed Parkin, also linked to PD, significantly decreased the death of substantia nigra brain cells.
“This indicates that techniques that alter the activity of the Parkin gene may represent a promising approach for the treatment of PD,” Dr. Aebischer suggests.
As a next step, the researchers are testing a large number of small molecules in the animal models to identify any that could prevent the development of PD.
silagra tablets
Another research group also used viral vectors to create improved animal models of PD. Deniz Kirik, MD, PhD, and his associates created a rat model and a monkey model of PD by using the viral vector technique to deliver the human alpha-synuclein gene to the dopamine-secreting brain cells located in the substantia nigra. They found that the affected cells were first functionally impaired and then slowly degenerated over several weeks. When the degenerative changes were most severe, behavioral impairments developed in the animals.
