Low-Hanging Fruit: Repurposing Drugs to Treat Retinal Diseases

Many years ago, while picking apples with my uncle, he advised me to “pick the low-hanging fruit.” That way, he told me, you can fill your basket faster and not be as tired at the end of the day. I think the same can be said of drug repurposing—the process of evaluating a drug prescribed for one disease to see if it can safely and effectively treat another disease.

One good example is valproic acid, or VPA, which was approved by the U.S. Food and Drug Administration (FDA) for treating epilepsy and bipolar disorders. Thanks to FFB-supported scientists, it is now being tested in clinical trials, or human studies, to evaluate its efficacy in treating a form of retinitis pigmentosa (RP). Because repurposing relies on prior research and clinical data, it reduces the cost and time needed to establish a new therapeutic application for the drug.

Dr. Nawajes Mandal, an assistant professor at the Dean McGee Eye Institute at the University of Oklahoma College of Medicine, thinks it might be possible to slow retinal degeneration with another FDA-approved drug. It’s known as Gilenya® and is used to treat multiple sclerosis(MS).

Dr. Mandal received his Ph.D. in lipid biochemistry in India, then worked in two FFB-funded facilities in the United States, one at the University of Michigan, the other at the University of Oklahoma. Aside from researching Gilenya®, he’s studying the role of fatty acids in retinal diseases and looking at other compounds that may serve as treatments.

Recently, I asked him a few questions about the Gilyena® project, which is funded by FFB.

Can you explain what Gilenya ® is and what it is used for?
It’s a drug that inhibits immune activation in lymphoid tissue. People with MS are thought to have an “overactive” immune system, and Gilyena® has been shown to be effective at reducing immune system flare-ups.

Why do you think it might be useful in treating retinal diseases?

We know that some retinal diseases, such as RP, may involve a secondary immune response, and so the direct immunosuppressant effects of Gilenya® may help in this respect. However, it has another interesting property. It is effective at inhibiting the production of a waxy lipid molecule known as “ceramide.”

So, what does ceramide have to do with retinal diseases?
In reviewing the scientific literature 10 years back, I found a paper that showed that ceramide levels increase in the mutant retina of fruit flies. I, therefore, decided to evaluate lipid profiles in the retina of normal and RP rodent models.

I was amazed when I found that, as in the fruit fly, ceramide levels increased in mammalian retinal cells that were undergoing programmed cell death, or apoptosis, which is caused by retinal diseases. So now, with FFB funding, I am trying to see if photoreceptor cells in various RP rodent models will survive longer if ceramide levels can be decreased using Gilenya®.

What have you found so far?
After evaluating the effects of Gilenya® in three different rodent models of RP, I found that, in each model, systemic administration was effective in decreasing retinal ceramide levels. As a consequence, the photoreceptor cells were protected.

What are your next steps?
Because of the systemic side effects of the drug, some of which can be harmful, I’m developing a topical formulation, or an eye drop. This way, the drug won’t enter the body. If Gilenya® eye drops are able to produce the same level of efficacy as the oral medication, I am hoping to apply to the Foundation Fighting Blindness’ Clinical Research Institute and the National Eye Institute for funding to support a clinical trial to evaluate the drops in humans with retinitis pigmentosa.