NIH Awards UF Researchers Major Grants To Study Gene Therapy In Array Of Disciplines

May 29, 1998

GAINESVILLE — In the much-heralded race to cure disease using gene therapy, scientists have struggled with a persistent problem: how to best ferry copies of healthy genes into the human body.

Now the National Institutes of Health has awarded two five-year grants totaling more than $11 million to University of Florida researchers studying one of the most promising gene delivery mechanisms – the adeno-associated virus, more commonly known in scientific circles as AAV.

Think of AAV as a car whose passengers are genes meant to correct their flawed or missing counterparts in people with an array of ailments, from cystic fibrosis to sight-robbing eye disorders such as retinitis pigmentosa. The money is slated for studies of the spinal cord, eye, heart and lung, as well as for research into other viral agents used for gene transport.

“Although it’s a great idea to cure disease with genes, and we can attack diseases we couldn’t attack before, we still didn’t have a reliable way of getting genes into the body,” said Nicholas Muzyczka, a professor of molecular genetics and microbiology at UF’s College of Medicine and the American Cancer Society Edward R. Koger eminent scholar. He also directs UF’s Gene Therapy Center. “So the NIH requested proposals to try to design new types of gene delivery vehicles, and one of those was AAV.”

UF researchers were scheduled to discuss some of their AAV-related research at the American Society of Gene Therapy’s annual meeting May 27-31 in Seattle.

UF’s interest in AAV dates to the late 1970s.

“UF has been involved in AAV virology for a very long time, and that’s why we have a natural strength in it here,” said Dr. Terry Flotte, an assistant professor of pediatric pulmonary medicine, molecular genetics and microbiology, and co-director of the Gene Therapy Center. “We’re now at the forefront in gene therapy, and our center has really taken a leading role.”

Two properties set AAV apart: It infects nondividing cells (the vast majority of the body’s cells are nondividing) without detectable side effects, enabling genes to be placed in a variety of organs, and it induces a very low immune or inflammatory response, so the genes inserted persist after just one application.

The following is a synopsis of the main projects slated to receive a portion of the funds from the National Institute of Neurological and Communicative Disorders and Stroke (more than $4.9 million):

• Paul J. Reier, an eminent scholar in the departments of neuroscience and neurosurgery at UF’s College of Medicine and the UF Brain Institute, is researching how to modify spinal cord cells to improve the success of spinal cord grafts, or actually modify spinal cord tissue to induce nerve cells to regenerate and reform the spinal cord.
• Alfred S. Lewin, a professor of molecular genetics and microbiology, and William Hauswirth, an eminent scholar and professor of ophthalmology, molecular genetics and microbiology, are using AAV-based gene therapy to fight a common inherited form of blindness. Known as retinitis pigmentosa, the condition affects hundreds of thousands of people worldwide.

They are using AAV to deliver corrected genes to the nervous system and slow retinal degeneration in rat and mouse models.

The National Heart, Lung, and Blood Institute funds (more than $7.2 million) are earmarked for several projects:

• Flotte is using AAV to transfer the alpha1-antitrypsin gene into muscle in mice, which are models for alpha1-antitrypsin deficiency, a problem associated with the development of emphysema.
• Dr. Barry Byrne, an assistant professor of pediatric cardiology, is studying the use of AAV for Pompe’s disease, a genetic disorder that affects the heart muscle.
• Lyle Moldawer, a professor of surgery, is collaborating with Richard Moyer, professor and chair of molecular genetics and microbiology. They are testing short-acting adenoviral vectors that express anti-inflammatory drugs, with the hope of treating life-threatening infections such as sepsis.
• M. Ian Phillips, professor and chair of physiology, and Mohan Raizada, associate dean of graduate education and a professor of physiology, are using AAV and other viruses to deliver genetic material they hope will control high blood pressure long-term without the use of drugs.
• Lung-Ji Chang, an associate professor of molecular genetics and microbiology, is striving to establish new vectors for UF’s Gene Therapy Center.
• Muzyczka is leading ongoing studies of AAV’s basic biology and is seeking ways to make AAV a better vector.

“Gene therapy is exciting,” Muzyczka said. “If it works, we’re looking at something that may be as powerful as organ transplantation, that would become a major medical procedure enabling us to do something about diseases we haven’t been able to touch so far.”