A Novel Antioxidant Therapy for Retinal Degeneration

Alfred Lewin, PhD
University of Florida (Gainesville, FL)

Co-Principal Investigators

Manas R. Biswal, PhD
University of Florida (Gainesville, FL)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2017
Disease:
Macular Degeneration
Award Amount:
$120,000
Grant Reference ID:
M2015348
Award Type:
Standard
Award Region:
US Southeastern

Recipient of The Elizabeth Anderson Award for Macular Degeneration Research.

Alfred Lewin, PhD

A Novel Antioxidant Therapy for Retinal Degeneration

Summary

Toxic oxygen compounds are known to damage the retina with age and to contribute to age related macular degeneration (AMD). We will use a mouse model of dry AMD (aka, geographic atrophy) to test if reversal of oxidative stress using gene therapy can be beneficial once signs of the disease are detected. Then we will test a potent antioxidant compound that we characterized previously to determine if it prevents retinal degeneration in these mice. Our goal is to prevent progression of dry AMD in people with early signs of this blinding disease.

Details

The goal of this project is to develop a novel drug to prevent geographic atrophy, the advanced form of dry AMD. Based on considerable biochemical and clinical data, we hypothesize that with age, normal metabolic activity produces reactive forms of oxygen that damage the retina.  We plan to test a newly discovered compound to prevent this damage in a mouse model of dry AMD in which the build up of reactive oxygen molecules is accelerated. This drug was selected in a high throughput screen of over 1.3 million compounds for its ability to stimulate the production of protective enzymes.

In our current experiments, we will do three things. First we will identify the best delivery method for the drug, for example, oral or injected or eye drops. Next, we will determine what dose of the drug is needed to elevate to level of protective enzymes in the retina. Finally, we will test the effective route of delivery and dose in the mouse model of AMD, employing some of the same techniques used in AMD in humans to measure protection, including measurements of retinal structure and function, and analysis of visual acuity. At the end of the experiments, histopathology will be performed to verify that protection has been achieved.

Our proposal is innovative in that we have access to large-scale screening used to identify drug compounds that offer retinal protection, and have identified several unique ones that have been tested for safety in cell culture and in animals. No one else working on the eye has these molecules.

About the Researcher

Alfred Lewin, PhD, is from Hammond, Indiana, where he was educated in the public schools. He attended the University of Chicago both for college and for graduate school, receiving a PhD in Biology in 1978. His research focus was on the basic molecular biology of mitochondria.  Dr. Lewin moved to Basel, Switzerland from 1978-1981, where he studied the importation of proteins into mitochondria. He continued these investigations at Indiana University in Bloomington, where he was assistant professor of chemistry. During this period, his lab turned to the study of catalytic RNA encoded by mitochondrial DNA.  In 1987, Dr. Lewin moved to the University of Florida College of Medicine, continuing his studies of RNA enzymes. In the early 1990's Dr. Lewin decided to put catalytic RNAs to work for human health, by designing small RNA enzymes, ribozymes, for the treatment of autosomal dominant forms of retinitis pigmentosa (RP). The strategy was to degrade the mRNA for mutant rhodopsin and to replace it with a normal form. These experiments were done in collaboration with William Hauswirth, PhD, and John Flannery, PhD, pioneers in retinal gene therapy, and Matthew LaVail, PhD, an expert on models of RP. 

While his research on RP continues vigorously, and is moving from rodents to larger animals, Dr. Lewin's group has recently turned its attention to AMD, using both a gene therapy and a pharmacological approaches.  Gene therapy is designed to block inflammation that is the hallmark of late stages of AMD. Drug therapy is intended to block oxidative stress that leads to that inflammation. These experiments are conducted first in cell culture and then in rodent models, but the goal is to develop treatments that are readily translatable to treatment of human patients.


"Lucky coincidences sometimes drive scientific decisions. If I did not have the lab across the hall from Bill Hauswirth, I would not have seen his poster describing successful gene transfer to the retina. If a clever MD-PhD student, Kimberly Drenser, hadn't joined my group I might not have helped her find clinically relevant research projects. If a research scientist, Xiaoping Qi, MD, hadn't accidentally misplaced a needle, we might not have developed a mouse model of dry AMD when we're intending to study optic neuropathy. These accidents all worked together to help us develop a mouse model of early AMD in which to test the drug therapy that is the subject of this project. One additional component was when our collaborator in medicinal chemistry, Hendrik Leusch, PhD, asked us to test a series of compounds he had discovered as natural products in seaweed to see if any had antioxidant properties in mice.  One of his compounds turned out be quite potent, and that is what we are testing in our mouse model of AMD."

Publications

Ahmed CM, Biswal MR, Li H, Han P, Ildefonso CJ, Lewin AS. Repurposing an orally available drug for the treatment of geographic atrophy. Mol Vis. 2016 Apr 2;22:294-310. eCollection 2016. PubMed Icon Google Scholar Icon
 

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