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By Denise Trunk

GAINESVILLE, Fla. - The National Institutes of Health recently awarded $5 million to University of Florida scientists who are harnessing gene therapy to improve sight and movement in millions of patients afflicted with genetic and acquired disorders.

Nicholas Muzyczka, Ron Mandel, William Hauswirth and Alfred Lewin, all Ph.D.s and members of UF's Genetics Institute and McKnight Brain Institute, are using different gene therapy techniques to identify and refine potential therapeutic treatments for a genetic eye disease and Parkinson's disease.

The NIH awards competitive program project grants to a group of scientists whose research program is unified by their use of a common resource, in this case, UF's Human Gene Vector Core facility, one of only a few public laboratories in the country capable of producing the highly clean virus used as the delivery vehicle in the three gene therapy projects.

The jerks and twitches of Parkinson's patients come from a lack of dopamine, a biochemical responsible for smooth muscle movement. Muzyczka is testing for the chemical signal that incites dopamine-producing brain cells to die. Mandel is testing how to prevent those cells from dying despite the chemical signal, and Hauswirth and Lewin are working together to eliminate a single gene that causes a form of genetic blindness.

Muzyczka, an eminent scholar and professor of molecular genetics and microbiology with UF's College of Medicine, is using gene therapy to flip chemical switches in the brain's circuit box to identify which breaker kills neurons in an area of the brain where Parkinson's occurs, the substantia nigra. His goal is to identify and turn off the chemical trigger that initiates cell death, and stop the progression of Parkinson's before it starts.

Muzyczka suspects a mysterious gene present at all nerve synapses, called alpha-synuclein, is involved in the death of dopamine-producing brain cells.

To test this, he is using the apparently harmless adeno-associated virus, AAV, to deliver alpha-synuclein in various doses to alternately trip switches in the mouse brain's relay system and examine the result.

Mandel, an associate professor of neuroscience, is using the AAV carrier to deliver a substance to the brain that bolsters dopamine-producing cells. Glial cell line-derived neurotrophic factor, or GDNF, was discovered in 1993. The brain makes the substance, and it somehow manages to keep alive dopamine-producing neurons that would otherwise die.

In previous research, Mandel has found GDNF succeeds in defending dopamine-producing cells in mice and nonhuman primates. At this stage, he is focusing on regulating GDNF's action in the brain and identifying a safe dosing method and conducting final preclinical studies required by the Food and Drug Administration before beginning work with human patients.

Mandel said GDNF would not be a cure for Parkinson's because it cannot reverse existing damage, but he said it would come close.

"In the best case, early onset patients would come in and be treated with GDNF and the disease would be stopped right there," Mandel said. "It gives patients the quality of life that approaches [a cure]."

Two of the UF professors of molecular genetics and microbiology, William Hauswirth and Alfred Lewin, are sending genetic smart bombs to kill dominant mutant genes that cause certain types of blindness, collectively called retinitis pigmentosa. Hauswirth said they use AAV to send the reagent, called a ribozyme, to the responsible gene pair in the eyes of dogs and mice, to zap the problem-causing gene and leave its normal partner gene untouched.

"We do not replace a gene with this type of gene therapy. If you just try to replace it, it wouldn't do any good because you would still have the bad copy there making toxic products," said Hauswirth, an eminent scholar. "Using ribozymes, we can actually precisely target the bad copy and destroy it."

With this grant Hauswirth and Lewin are refining the process for safety and dosing and preparing to take it to the FDA for clinical trials approval.

Kenneth I. Berns, M.D., Ph.D., director of the UF Genetics Institute and professor of molecular genetics and microbiology, said this illustrates the highlevel of collaboration at UF.

"It is a reflection of the high quality of our faculty as determined by peer review at the national level. It reflects the wisdom of our development of the UF vector core facility, which in fact is a national asset for AAV vector production," he said. "It demonstrates the advantages of cooperative effort which is enhanced by both the Brain Institute and the Genetics Institute, and it also represents research which promises to extend the results of basic research toward actual patient care."

UF vascular surgeon wins $1 million award to study scarring in vein bypass grafts

By Melanie Fridl Ross GAINESVILLE, Fla. - University of Florida vascular surgeon Scott A. Berceli, M.D., Ph.D., has received the prestigious 2004 Mentored Clinical Scientist Development Award, which includes a $1 million five-year grant for basic vascular biology research. Funded in part by a grant from the William J. von Liebig Foundation, the award is one of two given annually by the Lifeline Foundation and the National Heart, Lung and Blood Institute to support the development of outstanding clinician research scientists. It was presented June 5 at the 2004 Vascular Annual Meeting in Anaheim, Calif. Berceli is a previous winner of 1990 Liebig Foundation Award for excellence in vascular surgery research by a resident or fellow. Berceli, an assistant professor of vascular surgery at UF's College of Medicine and Gainesville's Malcom Randall Veterans Affairs Medical Center, is investigating the proteins that control scar formation within vein bypass grafts, a leading cause of heart attacks and limb loss. Better understanding of these processes ultimately could lead to improved disease prevention and treatment for patients, hesaid.