NIH Awards Nearly $2 Million to Fliesler for Eye Disorder Research

Steven J. Fliesler, PhD.

Steven J. Fliesler, PhD

Published January 31, 2012

Steven J. Fliesler, PhD, has been has awarded nearly $2 million from the National Institutes of Health (NIH) to support his research on Smith-Lemli-Opitz syndrome (SLOS), a hereditary eye disorder of cholesterol metabolism.

“Our goal is to use this model to test gene therapy strategies to ‘fix’ the gene defect and thus prevent the retinal degeneration.”
Steven J. Fliesler, PhD
Meyer H. Riwchun Endowed Chair Professor of Ophthalmology, vice chair and director of research in the Department of Ophthalmology

Fliesler, the Meyer H. Riwchun Endowed Chair Professor of ophthalmology, has conducted pioneering studies on SLOS-associated retinal dysfunction and degeneration.

This latest award—a four-year RO1 grant renewal of $1,955,000—marks 19 consecutive years of NIH funding for his research.

Created Viable Laboratory Model for SLOS

Using an experimental drug created in the 1960s for lowering blood cholesterol but never approved for human use, Fliesler and his colleagues developed a rat model that closely mimics the key biochemical and neurological abnormalities of SLOS.

These abnormalities include a dramatic reduction in cholesterol levels and replacement with its immediate precursor, 7-dehydrocholesterol (7DHC), in all bodily tissues.

Studies Aim to Prevent Retinal Degeneration

The UB team is currently working with the model to further elucidate the molecular mechanism underlying SLOS, with an emphasis on the cause of retinal degeneration.

“Our hypothesis is that the formation and accumulation of 7DHC—which is extremely sensitive to oxidation—leads to the formation of toxic oxysterols that cause retinal cells to be dysfunctional and eventually kill them, resulting in the observed degeneration,” Fliesler explains.

Collaborating with colleagues at Vanderbilt University, Fliesler’s lab has shown that several 7DHC-derived oxysterols accumulate in the retina and other tissues in the rat model.

If the hypothesis is correct, an antioxidant cocktail might stop toxic oxysterols from forming, thereby preventing or reducing the severity of retinal degeneration.

“Simply providing dietary cholesterol to overcome the blocked step in cholesterol synthesis is not very effective,” Fliesler notes. “Based on our results, we propose that a combined high-cholesterol/antioxidant regimen may provide a better therapeutic intervention for this disease.”

Due in part to Fliesler’s animal-model studies, researchers at Children’s Hospital Colorado are conducting a pilot clinical trial to test this hypothesis in children with SLOS.

In further related studies, the UB researchers are systematically testing various 7DHC-derived oxysterols on cultured retina-derived cells in the laboratory to see which are toxic to the retina.

Once this is ascertained, they plan to test a range of oxysterols in laboratory models to determine if certain oxysterols cause retinal degeneration similar to what they previously observed.

Exploring Potential Gene Therapy Strategies

Fliesler and his team also are developing a novel, genetically modified line of mice in which they have selectively disrupted the cholesterol pathway in either rod or cone photoreceptor cells or in other retinal cell types. With this line, they expect to learn whether  pathway disruption leads to the type of retinal degeneration they saw in their pharmacologically-induced rat model.

“Our goal is to use this model to test gene therapy strategies to ‘fix’ the gene defect and thus prevent the retinal degeneration,” Fliesler says. “This will provide an important preclinical proof-of-principle demonstration of the potential utility of this approach to treat SLOS in humans.”

More Than Three Decades of Research, Collaboration

Fliesler, a research health scientist at the Buffalo VA Medical Center and vice chair and director of research in the UB Department of Ophthalmology, has been researching cholesterol metabolism in the retina for more than three decades, beginning with his PhD thesis at Rice University.

Key collaborators on his studies include: Libin Xu, PhD, and Ned A. Porter, PhD, at Vanderbilt; Shailendra Patel, MD, at the Medical College of Wisconsin; Aimee Stablewski at Roswell Park Comprehensive Cancer Center; and Eduardo Sollessio, PhD, at SUNY Upstate Medical Center.