A New Dry AMD Target?

Dry AMD – it’s one of ophthalmology’s modern mysteries. And it represents a huge unmet need; there are currently no available treatments for the disease, and recent hopeful candidate lampalizumab failed to meet its primary endpoint at Phase III (1). Because the mechanisms driving disease progression remain elusive, sourcing candidates is tough. But now, there is a new lead to chase: cGas.

cGas – or cyclic GMP-AMP cyclase – is a DNA sensor enzyme that is thought to function in the immune response to viruses. A multicenter team have, however, identified that the enzyme may also play a role in dry AMD disease progression by driving interferon signaling, which leads to mitochondrial-damage-induced inflammasome activation and, ultimately, retinal pigmented epithelium (RPE) degeneration (2). Jayakrishna Ambati from the Center for Advanced Vision Science at the University of Virginia, USA, and corresponding author on the associated publication shares the details.

What inspired your recent research direction?

Previously, we demonstrated that the inflammasome is a critical driver of retinal cell death in dry macular degeneration (3). We sought to determine the precise mechanisms by which inflammasome activation occurs in this disease, which led us to discover that activation occurred via the “non-canonical” Caspase-11 pathway.

What impact could your work have on the management of dry AMD?

Our work identifies cGAS as an extremely early event in the process by which retinal cells die in macular degeneration, which provides a strong rationale for developing therapies that can block cGAS or its effects. In addition, there is also potential to develop new imaging technologies to directly image inflammasome activation in the living human eye, which could identify patients with active disease who might be ideal candidates for therapy, as well as provide a means of monitoring treatment activity.

Did you suspect cGAS from the outset?

No. We were surprised because cGAS is a viral sensor, and there is no apparent viral involvement in macular degeneration.

Next steps?

Previously, we demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs; a class of drugs already on the market for treatment of HIV/AIDS and hepatitis B), and modified NRTIs known as Kamuvudines, block inflammasome activation and prevent retinal death in relevant models of dry AMD (4). Inflammasome Therapeutics has licensed this technology and is moving rapidly to commercialize it. It turns out that NRTIs and Kamuvudines also block the function of cGAS and the non-canonical inflammasome as they relate to dry macular degeneration; hence, we are investigating the mechanisms by which these drugs have these multifaceted effects.