Stoke Advances ASO Therapy Targeting OPA1 in ADOA

Stoke Therapeutics (Stoke), a Beford, Mass.-based biotechnology company, has dosed the first patient in a Phase I clinical study (OSPREY) evaluating STK-002, an investigational antisense oligonucleotide (ASO) designed to treat autosomal dominant optic atrophy (ADOA), a rare inherited optic neuropathy characterized by progressive and irreversible vision loss. The open-label, dose-escalation study will assess safety, tolerability, and systemic exposure in children and adults with genetically confirmed OPA1 variants.

ADOA is the most common inherited optic nerve disorder, affecting approximately one in 30,000 individuals globally. The disease is typically driven by haploinsufficiency of the OPA1 gene, resulting in reduced OPA1 protein expression and subsequent degeneration of retinal ganglion cells. Approximately 80% of affected individuals develop symptoms by age 10, and up to half progress to legal blindness. There are currently no approved therapies (1,2).

“Data from our natural history study suggest that for some people affected by ADOA, the disease progresses more rapidly than previously thought,” said the lead principal investigator of the study, Patrick Yu-Wai-Man, MD, PhD, professor of Ophthalmology at the University of Cambridge and honorary consultant neuro-ophthalmologist at Addenbrooke’s Hospital, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, United Kingdom (UK), in a company press release (1). “Based on a growing understanding of the disease biology, we believe that increasing naturally occurring OPA1 protein may help restore vision in people with ADOA.”

What is the rationale for targeting OPA1 in ADOA?

STK-002 is designed to increase production of OPA1 protein by leveraging the non-mutant allele of the gene. The approach is based on Stoke’s Targeted Augmentation of Nuclear Gene Output (TANGO) platform, which aims to restore naturally occurring protein expression in diseases caused by haploinsufficiency. An estimated 65% to 90% of ADOA cases are linked to OPA1 variants that reduce protein levels by approximately 50% (1,3).

Preclinical data generated by the company demonstrated proof-of-mechanism and proof-of-concept for OPA1 protein upregulation, supporting advancement into human studies. STK-002 has received orphan drug designation from FDA.

“There are currently no medicines available for people living with ADOA, and there is a lot of interest in this study from the ADOA community given the potential for STK-002 to restore vision by addressing the root cause of the disease,” Dr. Yu-Wai-Man stated in the release.

How is the Phase I OSPREY trial designed?

The OSPREY study is enrolling participants aged six to 55 years with confirmed OPA1 mutations across sites in the UK and Germany, with additional European sites expected to initiate in the coming months, according to the company. The trial follows a sequential cohort, single ascending dose design. Primary endpoints include safety, tolerability, and systemic exposure. Secondary endpoints assess changes in visual function, ocular structure, and quality of life. The company plans to carry out dose escalation of the first four cohorts through 2026 and early 2027, contingent on safety evaluations.

“ADOA is a haploinsufficient disease, one of many that we believe are ideally suited for our ASOs that are designed to increase naturally occurring protein levels to improve health,” said Barry Ticho, MD, PhD, chief medical officer, Stoke Therapeutics, in the release (1). “We are pleased to be expanding our approach into a new disease area, leveraging our learnings from Dravet syndrome and applying them to the development of a potential disease-modifying medicine for people living with ADOA.”

The initiation of dosing represents an expansion of Stoke’s RNA-based protein restoration strategy beyond central nervous system indications into inherited ophthalmic disease. If successful, the program could provide clinical validation for antisense-mediated augmentation of endogenous protein expression in ocular haploinsufficiency disorders, an area where no disease-modifying treatments currently exist (3).

References

1. Stoke Therapeutics. Stoke Therapeutics Announces First Patient Dosed in Phase 1 Study of STK-002, a Potential Disease-Modifying Medicine for the Treatment of Autosomal Dominant Optic Atrophy (ADOA). Press Release. Feb. 11, 2026.
2. Yu-Wai-Man, P.; Griffiths, P. G.; Burke, A.; et al. The Prevalence and Natural History of Dominant Optic Atrophy Due to OPA1 Mutations. Ophthalmology 2010, 117 (8), 1538–1546.e1. DOI: 10.1016/j.ophtha.2009.12.038
3. Wong, D. C. S.; Harvey, J. P.; Jurkute, N.; et al. OPA1 Dominant Optic Atrophy: Pathogenesis and Therapeutic Targets. J Neuroophthalmol. 2023, 43 (4), 464–474. DOI: 10.1097/WNO.0000000000001830