New Research Shows Viruses Can Be Harnessed to Understand and Treat Disease
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NR-11-05 (11/15/05). For more information, please contact Sara Harris at (202) 462-6688 or sharris@sfn.org.
NEW RESEARCH SHOWS VIRUSES CAN BE HARNESSED TO UNDERSTAND AND TREAT DISEASE
WASHINGTON, DC, November 15, 2005 — Cursed for causing colds, scientists are now exploring ways to harness viruses to understand and treat disease. New research finds that techniques using stripped down altered viruses, termed viral vectors, create improved animal models of disease and also hold promise in treating serious neurological ailments.
“New studies show that new viral vector techniques can be used to develop improved models of neurodegenerative diseases, which can aid in the understanding of disease and the development of treatments,” says Anders Bjorklund, MD, of the University of Lund in Sweden and the chair of a symposium on viral vectors at this meeting. “The strategy is also directly being used as a successful new approach for therapy.”
Specifically, the viral vector technique relies on the knack of viruses to invade cells and transfer genetic material. While a cold virus would transfer cold-producing genetic material, viral vectors are made of stripped down viruses that are altered to transfer genetic material that can reproduce the effects of a certain neurological disease in an animal model, or on the treatment side, transfer genetic material that can stop the biological mechanisms that underlie a neurological disease.
One new study finds that a new viral vector technique improved movement and cellular abnormalities normally seen in mice that model Huntington's disease (HD), a movement disorder that affects an estimated 30,000 Americans. “Our findings that our viral vector technique can have a profound impact on the cellular and motor characteristics of HD in a mouse model are very exciting,” says Beverly Davidson, PhD, of the University of Iowa.
A person’s genes produce proteins that control brain development and function. In HD, however, a faulty version of a gene, termed huntingtin, produces a flawed protein, which somehow makes the system go awry. As a result, people that have 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 experience involuntary movements of the arms, legs, body, and face. Often these symptoms are accompanied by mood swings, depression, irritability, slurred speech, and clumsiness. While the disease progresses, the afflicted can have problems swallowing, 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 Davidson. Instead, 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,” says Davidson. “If we can get rid of the flawed protein, we should have a great impact on the disease.”
In the study, the researchers found that the technique reduced the flawed huntingtin levels to 40 percent of pretreatment levels. In addition, normally the flawed huntingtin protein forms clumps in cells. Their technique, however, reduced these clumps. In addition, the reduction in protein levels correlated with improvements in movement problems seen in the HD mice such as wavering when they walk, 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,” says Davidson.
The mouse model that the researchers used demonstrates disease symptoms very early. As a next step, the researchers plan to test the therapy in a model that more closely resembles human HD where the symptoms are more subtle, and take many more months to appear.
Other researchers have developed new and improved animal models with the aid of viral vector techniques. “The use of viral vectors to create animal models of central nervous system pathologies holds various advantages compared to the classic, transgenic approach that involves breeding animals with an abnormal, disease-contributing gene produced in a specific organ or subset of cells,” says Nicole Déglon, PhD, of the Atomic Energy Commission in Orsay, France. “Viral vectors allow us to make multiple genetic models in a short period of time and the technique provides a rapid appearance of functional and behavioral abnormalities and severe neurodegeneration.” In addition, the technique allows researchers to specifically target the function of specific brain areas. “Targeted injections in different brain areas can be used to investigate the regional specificity of the neuropathology and eliminate potential side effects associated with a widespread effect that is seen in the traditional models,” says Déglon. “Finally, we can use virus vector techniques to create models in a variety of different mammalian species including non-human primates, thereby providing an opportunity to assess complex behavioral changes and perform long-term follow-up of neuropathological alterations with brain imaging.”
Most recently the researchers used a viral vector technique to create a non-human primate model of HD. First they found in adult rats that a viral technique that 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. Then they found that in addition to these problems, non-human primates injected with the viral vector also showed behavioral deficits associated with HD.
“The animals show an increase in locomotor activity and abnormal movements that are similar to HD,” says Déglon. “These data indicate that our viral vector technique creates an animal model that provides a flexible setting to dissect the relationships between motor deficits, brain cell dysfunction, and the occurrence of cell death in HD.”
In parallel to these studies, the researchers are also testing the use of viral vectors to treat pathologies. For example, they are developing a viral vector-based RNA interference technique like Davidson’s that may block or delay the appearance of HD symptoms.
Other researchers used the viral vector technique to create animal models of Parkinson’s disease (PD), which helped them identify ways to treat the movement disorder. About 50,000 Americans are diagnosed with Parkinson's disease each year, with more than half a million Americans affected at any one time, according to the National Institute of Neurological Disorders and Stroke.
“Our studies validate the viral-based genetic model of PD as a powerful tool to both allow a better understanding of the disease and to screen various therapeutic approaches,” says Patrick Aebischer, MD, of Ecole Polytechnique Fédérale de Lausanne in Switzerland.
PD is characterized by slow movements, tremors, muscle rigidity, as well as 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 the disease is the presence of clumps in degenerating brain cells, termed Lewy bodies. Several mutated genes have been linked to forms of PD, including two that affect a protein termed 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 Aebischer.
In new work, Aebischer and his colleagues developed an animal model of PD that targets alpha-synuclein with viral vector approaches. “The classic transgenic mouse models based on the overexpression of human alpha-synuclein only show mild neuropathology with occasional clumps that represent Lewy bodies, but no loss of dopamine cells in the substantia nigra,” says Aebischer. “To overcome this lack of cellular degeneration in rodents, we investigated an alternative approach for developing genetic models of PD that used viral vectors.” Using the viral vector approach researchers were able to inject mutated forms of the alpha-synuclein gene into the brain region of rats affected in the human disorder. “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 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,” says Aebischer.
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.
Another research group also used viral vectors to create improved animal models of PD. “With these new models we are now able to gain a better understanding of the progression of the disease and we also have better opportunities to apply new therapeutic strategies,” says Deniz Kirik, MD, PhD, of the University of Lund in Sweden.
Kirik and his colleagues created a rat as well as 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, which is effected by PD. They found that the affected cells were first functionally impaired and then slowly degenerated over several weeks. In cases where the degenerative changes were most severe, it led to the development of behavioral impairments in the animals.
