Rochester University researcher awarded 2017 Shaffer Prize

For his research efforts to better understand the molecular pathways that are responsible for axonal degeneration in glaucoma, Richard Libby, PhD, was awarded the 2017 Shaffer Prize for Research during Thursday night’s Glaucoma 360 annual Gala. 

The project could result in the identification of novel molecular targets that would allow clinicians to slow or halt axonal degeneration in retinal ganglion cells and stop the progression of glaucoma.

Dr. Libby

Dr. Libby received the award for his study, “Understanding Axonal Degeneration Pathways in Glaucoma.” Dr. Libby is associate professor of ophthalmology, Flaum Eye Institute, University of Rochester Medical School, Rochester, NY.

Thomas Brunner, president and chief executive officer of the Glaucoma Research Foundation (GRF), presented the award. The Shaffer Prize is presented annually by GRF to a researcher whose project best exemplifies the pursuit of innovative ideas in the quest to better understand glaucoma.

“The likely major cause of glaucoma is injury to the axons in retinal ganglion cells,” Dr. Libby explained. “We know that axon injury has its own unique degeneration pathway, but we don’t know many of the molecules that are involved.

“What we have shown is that a particular molecule, SARM1, is part of the axonal degeneration cascade in retinal ganglion cells,” he added. “This is a first step in understanding the axonal degeneration pathway. Once we understand the pathway, we can design a drug that stops axonal degeneration early in the process and, we hope, prevent the progression of glaucoma.”

14 years in the making

14 years in the making

Using funds from the Shaffer Grants to Innovative Glaucoma Research in 2015, Dr. Libby has been able to begin unraveling the molecular pathway that controls axonal injury signaling and axonal degeneration leading to the neurodegeneration and the resulting loss of vision that is glaucoma.

There are currently no drugs or other therapies directly aimed at neuroprotection in glaucoma. That means patients have limited treatment options to prevent the progression of vision loss that is typical of glaucoma.

Understanding how retinal ganglion cells are injured, degenerate, and ultimately die is a long-term undertaking. Dr. Libby’s search for the pathway, leading to axonal degeneration and glaucoma, began about 12 years ago in the laboratory of Simon John, PhD, professor and Howard Hughes Medical Investigator, Jackson Laboratory, Bar Harbor, ME.

Researchers found a mouse mutant that was known to lessen axonal degeneration and protected the incidence of glaucomatous neurodegeneration in an ocular hypertensive model of glaucoma. What no one knew was how this mutation worked to protect retinal ganglion cell axons.

As the cell biology of axons was explored, researchers began to identify specific molecules that are present at different times during the life cycle of retinal ganglion cells. Dr. Libby hypothesized that a molecule that was known to play a role in axonal degeneration in other systems, SARM1, could be critical for axonal degeneration in retinal ganglion cells.

Cells follow pathway

Cells follow pathway

Retinal ganglion cells, like other cells in the body, live and die by following specific molecular pathways. These pathways cascade from one step to the next.

By working up the cascade from any starting point, it is possible to understand what causes a particular molecule, such as SARM1, to become active. Working down the cascade shows what that same molecule causes to happen later in the pathway. Working through the cascade, step by step, can be a slow process.

Dr. Libby said it has been clear for some time that one way to control glaucoma is to block the cascade that leads to axonal injury, axonal degeneration, and retinal ganglion cell death. It was recognized that axonal injury is an early and important event in the development of glaucoma.

However, no one knew how axonal degeneration progressed. The identification of SARM1’s role in retinal ganglion cell axonal degeneration is an early step in determining the degeneration cascade that leads from axonal injury to vision loss in glaucoma.

“When we removed SARM1, we significantly delayed axonal degeneration,” Dr. Libby said. “That suggests it plays an active role in causing, or least in promoting, axonal degeneration. The next step is to figure out what turns that molecule on.”

Potential therapies

The pathways that guide and direct axonal degeneration were all but unknown 10 years ago and are slowly becoming understood. Because removing SARM1 appears to reduce axonal degradation and protect against the development of glaucoma, finding a way to block one or more steps in the pathway leading to axonal death offers the promise of neuroprotection. Inhibiting SARM1 or inhibiting earlier steps in the pathway that lead to SARM1 could become a powerful therapeutic approach to treating glaucoma.

It is still too early to talk about a specific therapy, Dr. Libby said. But for the first time, there is the clear potential for a treatment that could directly slow or even stop the axonal damage that leads to glaucoma.

“The real key is that we are starting to define the endogenous molecules inside axons that are critical for degradation,” he said. “It is a first step in understanding and stopping the axonal degradation cascade in glaucoma. We have to understand that cascade in order to get at the heart of the disease and rationally design a treatment that goes to the nerve degeneration that results in glaucoma.”