Gene Transfer

Gene transfer methods were initially thought of as having the 188, greatest potential benefit in the treatment of diseases caused by a single genetic flaw, such as Huntington's disease or sickle cell anemia. Multifactorial diseases, such as Alzheimer's, are not ideal targets for gene transfer methods because they are caused by a profoundly complex interplay among multiple genes and environmental factors. However, scientists are experimenting with a variety of ways to treat neurodegenerative disorders by using genetically altered tissues to effect repair or enhance function in areas of the brain that are important for memory.

Brain disorders pose special problems for standard gene transfer techniques. Although most gene transfer methods utilize a harmless, neutralized virus as a vector, or delivery system, for transporting genetic material into targeted cells, viral vectors are typically too large to pass through the natural protection of the blood-brain barrier in order to reach target areas in the brain. Alternative transfer methods for targets in the brain are being investigated, including direct injection and the use of liposomes (fatty spheres) as transport vehicles.

Researchers at the University of California, San Diego, developed a method of genetically modifying skin cells to express nerve growthfactor (NGF), a protein that helps neurons survive by repairing damage and stimulating their regeneration. Beginning in 2001, modified skin cells taken from eight patients with mild Alzheimer's disease were implanted into brain structures in which cholinergic cells are typically destroyed by Alzheimer's disease.

Researchers reported in 2004 that the surgery was successfully completed in six patients and appeared safe and well tolerated. Two of the eight patients had complications during the injection, leading to a modification of the original procedure. PET scans showed increased metabolic activity in areas of the brain with the implants compared with activity in the brains of similar patients without implanted cells, suggesting that NGF had produced a positive physiological effect. In addition, the annual rate of cognitive decline was reduced by 40 to 50 percent in the implanted patients, which is significantly better than the typical response to currently available medications. Ceregene, the company sponsoring this research, plans for further clinical trials on genetically ,189

modified skin cell implants at Rush University Medical Center in Chicago.

Genetic methods might one day prevent memory problems altogether and endow us with superior memories. One potential target for genetic modification is the NMDA receptor, a neuronal docking point for specific neurotransmitters involved in learning and memory. In 1999 scientists at Princeton University, the Massachusetts Institute of Technology, and Washington University reported on research in which they were able to produce a genetically altered strain of "smart" mice with extra NMDA receptors. In experiments, these mice learned and remembered better than their genetically "normal" counterparts.

Scientific concerns are significant, associated with the unforeseen future impact of gene transfer on the human genome. In fact, one gene transfer clinical trial was stopped after a child developed leukemia, possibly as the result of a genetic mutation caused by an unanticipated interaction between the therapeutic genetic material and other genes. The future success of gene transfer methods depends in part on refining techniques for precise delivery of genes to targets, thereby preventing unintended genetic interactions.

One day, it may be possible to use gene therapy to enhance memory and other cognitive functions in people who are healthy. Profound ethical issues arise when we consider the implications of genetically enhancing normal individuals or selectively engineering desirable characteristics in humans. Compelling arguments can be made on either side of this issue.

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