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Researchers at the National Institute on Aging (NIA) have developed a process that uses a virus to transport needed DNA fragments to chemically deficient sites in the brains of laboratory animals. This process has the potential to be a first step toward reversing deficiencies in the brains of humans with various age-related neurological diseases, such as Huntington's disease and Parkinson's disease. The new research, reported in the January 1996 issue of Molecular Brain Research, gives hope that, from this first step in the laboratory, a gene therapy in humans could be developed which would be much more effective and longer lasting than currently limited drug therapies, such as L-dopa for Parkinson's disease.
This research was headed by Drs. George Roth and Donald Ingram at the National Institute on Aging's Gerontology Research Center in Baltimore, MD, in collaboration with Drs. Andrea Mastrangeli and Ronald Crystal of Cornell University Medical School. Drs. Roth and Ingram's team used an inactivated adenovirus to help with the transfer of a DNA fragment necessary for repairing a neurotransmitter receptor deficiency in the brain of rats. The transferred DNA was successfully incorporated into the rats' own DNA, which was then able to produce a protein that served as a receptor for the neurotransmitter, dopamine.
Neurotransmitters are chemicals that carry messages between nerve cells. Dopamine, a neurotransmitter associated with the regulation of complex movements, is severely depleted in diseases such as Parkinson's. The number of dopamine receptors is also severely diminished in the brains of people with Huntington's disease when there is neurodegeneration in areas usually rich in this receptor. Normal aging is also accompanied by a continuous loss of dopamine receptors in this same brain region called the neostriatum. Furthermore, loss of these receptors appears to be associated with motor dysfunction.
The researchers found a marked increase in the concentration of the dopamine receptors in the treated areas of the rat brain when compared to levels found in the brains of the control rats. Results of tests done with cells in laboratory dishes help to reinforce results from live rat experiments. These tests showed a nearly twofold increase in receptor binding by the virally borne DNA as opposed to what was found in control dishes. Put together, the findings from the live rat and laboratory dish experiments point to a potential of developing other viruses which could be modified to deliver DNA to neurotransmitter vector receptors that are lost in other brain diseases. The goal is to develop a virus which could reach the brain and bring about reversals in neurotransmitter deficits in humans. Drs. Ingram and Roth's viral research points towards a promising new approach in treating neurological diseases.
The NIA research team includes Drs. Hiroyuki Ikari, Liang Zhang, Hui Kuo and Jeffrey M. Chernak. The National Institute on Aging, a component of the National Institutes of Health, is the lead Federal agency supporting and conducting research on the aging brain, including studies of the basic, clinical, and epidemiological aspects of Alzheimer's and other related dementias of aging.
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