New Developments in ADOA Research: ASHA Therapeutics' Approach to Slow and Partially Reverse ADOA
by Peter Makai
In late April 2025, some volunteers from the Cure ADOA Foundation and ADOAA (our American sister organization) met with some representatives from ASHA Therapeutics. ASHA Therapeutics unveiled promising research on two new drug candidates to intervene in the disease process caused by mutations in the OPA1 gene. Their strategy focuses on two key biological mechanisms that are activated by mitochondrial dysfunction in ADOA.
About ADOA
Autosomal Dominant Optic Atrophy (ADOA) is a genetic disorder that causes progressive vision loss, usually beginning in childhood or early adulthood. This condition is primarily caused by mutations in the OPA1 gene, which is critical for maintaining the structure and function of mitochondria—the powerhouses of the cell.
When OPA1 is mutated, mitochondria become fragmented and inefficient, leading to energy disruptions. This is especially damaging to retinal ganglion cells (RGCs), the nerve cells that connect the eye to the brain. As mitochondrial dysfunction worsens, these cells degenerate, leading to thinning of the optic nerve and irreversible vision loss.
In some cases, known as ADOA-plus, patients may also experience additional symptoms such as hearing loss and muscle weakness, suggesting a broader vulnerability of the
nervous system.
ASHA 624
The first mechanism involves a protein called SARM1 (Sterile Alpha and TIR Motif Containing 1). Under stress, SARM1 is activated and NAD+, a molecule vital to cell survival, is depleted. This leads to a so-called “metabolic catastrophe,” in which the cell’s energy reserves are depleted and cell death occurs.
In a mouse model with an OPA1 mutation similar to that of ADOA patients, researchers found that timely deletion of the SARM1 gene reversed optic nerve degeneration and vision loss. Based on this finding, ASHA Therapeutics developed ASHA 624, a small molecule drug designed to inhibit SARM1 by locking it in its inactive form. Unlike previous methods that risked accidentally removing SARM1
activated, ASHA's approach uses an “intramolecular glue” strategy to
to stabilize the protein in its harmless state.
The primary goal of this therapy is to stop further deterioration of optic nerve cells. Encouragingly, there is some evidence that early treatment may allow some recovery even if the cells are not completely dead. Research suggests that marginally functional or damaged cells may be able to regenerate their axons—the long fibers that carry visual signals—if the destructive activity of SARM1 is blocked.
Early intervention could therefore not only preserve existing vision but also lead to some improvement, especially in younger patients whose nervous system still has regenerative capacity.
ASHA 091
The second therapeutic target is the protein DRP1 (Dynamin-Related Protein 1), which drives mitochondrial fragmentation. Normally, there is a balance between mitochondrial fission and fusion in healthy cells. However, in ADOA, loss of OPA1 function disrupts this balance, which then causes excessive fragmentation. DRP1 becomes overactive, exacerbating energy failure.
The second drug, ASHA 091, inhibits the GTPase activity of DRP1, restoring a healthier mitochondrial network and improving overall energy production in cells. Blocking DRP1 not only changes the physical structure of mitochondria, but also restores critical functions such as ATP production, maintenance of membrane potential, and reduction of damaging oxidative stress, all of which are essential for keeping optic nerve cells alive and functional.
Both ASHA 624 and ASHA 091 are being developed as oral medications, making them easily accessible and able to reach the entire nervous system, which could also help patients with systemic ADOA-plus symptoms.
Findings
Early safety studies are promising. ASHA 624 has shown a wide margin of safety in animal models, effective at low doses and safe even at much higher doses. Inhibiting SARM1 is
considered low risk because this protein has no essential function in healthy adult tissues, other than its role in immune responses to rare viral infections. Furthermore, ASHA 091 has not shown significant toxicity in preclinical studies to date.
Continuation
ASHA Therapeutics plans to begin human clinical trials later this year. Their current work involves testing both compounds in both patient-derived cell models and specialized mouse models that closely mimic human ADOA. If successful, these therapies could provide the first treatment for ADOA.
While it is premature to promise a cure, the possibility of halting further degeneration of the optic nerve and potentially saving some vision is a major breakthrough for patients and families suffering from ADOA and ADOA-plus.
The introduction of such therapies could also change the diagnostic landscape. The availability of a treatment will likely lead to earlier detection of ADOA, giving patients the best chance to preserve and protect their vision at an earlier stage of the disease.
