Autosomal dominant optic atrophy (ADOA), the most common genetic optic neuropathy, is an insidious disease. It often presents slowly during childhood by way of blurry vision, trouble reading or focusing, and sometimes only as a failed vision test. But behind these subtle signs lies progressive, irreversible vision loss in both eyes caused by deterioration of retinal ganglion cells (RGCs) — the neurons responsible for carrying information from the eyes to the brain. In most cases, the damage is linked to mutations in the OPA1 gene, which interfere with mitochondrial function (how cells make energy and stay healthy).
New research led by Thomas Schwarz, PhD , and Chen Ding, PhD , of the Schwarz Lab at Boston Children's Hospital , has identified a promising therapeutic target to stop the damage to RGCs. Interestingly, ADOA wasn't even on their radar until 2019 when a family whose daughter is genetically at risk for the disease approached the lab with a powerful ask: Could their research on mitochondrial dysfunction be applied to ADOA and help save her sight?
The question put a face to the team's research, and the family's support helped push an idea into a promising treatment strategy.
"It caused us to put our heads together and ask what meaningful work we might undertake to help," Schwarz says.
A promising target
The Schwarz Lab's study, recently published in the Journal of Clinical Investigation , shows that deleting or disabling a single protein — SARM1 — can preserve RGCs and maintain vision in a mouse model.
SARM1 is known to trigger axon degeneration — the process by which the signal-sending part of a nerve cell breaks down. In ADOA, it's the activation of this process that leads to damage in the retinal ganglion cells.
"Most treatments for neurodegenerative diseases like ADOA aim to keep cells alive or slow the progression of damage," says Ding. "What we've found is a molecular off-switch of sorts for the process that causes these cells to die in the first place."
When the researchers removed SARM1 from the mice carrying the OPA1 mutation, the RGCs remained functional, and the mice retained their vision.
"In a field where we've had so few effective interventions, this a big thing," says Schwarz.
From gene discovery to drug design
With support from the girl's family and a grant from Advancium Health Network — a public charity helping advance therapies for rare disease — the Schwarz Lab is now testing whether SARM1 can be turned off with therapeutics, not just through genetic manipulation.
"If the SARM1 inhibition we're testing in the lab now is effective, the next step will be to see if inhibiting it in patients can deliver the same nerve-protecting effects," says Ding. To do this, the team will evaluate ASHA-624, a new drug designed to block SARM1 by locking the protein into an inactive state, preventing it from triggering axonal degeneration.
What comes next
For physicians caring for children with ADOA — and for families, Schwarz and Ding believe now is a pivotal moment. As SARM1-targeted treatments move closer to clinical trials, they say early genetic diagnosis will be critical in identifying patients who could benefit from future treatments, giving them a real chance of preserving their vision rather than simply slowing its loss.
"SARM1 inhibition is a new way to think about ADOA," says Schwarz. "We hope that a therapy is within our reach, and we want to move it forward as fast as we can."
