Stoke Therapeutics Initiates First-in-Human Trial of STK-002 for Rare Genetic Eye Disease ADOA
核心洞察
Stoke Therapeutics has dosed the first patient in the Phase 1 OSPREY study of STK-002, an antisense oligonucleotide designed to treat Autosomal Dominant Optic Atrophy (搜索) (ADOA (搜索)).
ADOA (搜索) is the most common inherited optic nerve disorder affecting approximately one in 30,000 people globally, causing progressive vision loss with no currently approved treatments.
STK-002 aims to restore OPA1 (搜索) protein expression by targeting the underlying genetic cause of ADOA (搜索), potentially becoming the first disease-modifying therapy for this condition.
Stoke Therapeutics has achieved a significant milestone in rare disease drug development by dosing the first patient in the Phase 1 OSPREY study of STK-002, an investigational antisense oligonucleotide (ASO) for treating Autosomal Dominant Optic Atrophy (搜索) (ADOA (搜索)). The announcement marks the beginning of clinical testing for what could become the first disease-modifying therapy for this devastating inherited eye condition.
Addressing an Unmet Medical Need
ADOA (搜索) represents the most common inherited optic nerve disorder, affecting approximately one in 30,000 people globally, with a notably higher incidence of one in 10,000 in Denmark due to a founder effect. The disease causes progressive and irreversible vision loss in both eyes, typically beginning in the first decade of life. According to the company, approximately 80 percent of people with ADOA are symptomatic by age 10, and approximately half are expected to become legally blind.
"Data from our natural history study suggest that for some people affected by ADOA (搜索), the disease progresses more rapidly than previously thought," said Dr. Patrick Yu-Wai-Man, M.D., Ph.D., the lead principal investigator and Professor of Ophthalmology at the University of Cambridge. "Based on a growing understanding of the disease biology, we believe that increasing naturally occurring OPA1 (搜索) protein may help restore vision in people with ADOA."
The severity of ADOA (搜索) varies significantly, with approximately half of affected individuals failing driving standards and up to 46% registered as legally blind. More than 400 different disease-causing OPA1 (搜索) variants have been reported in people diagnosed with ADOA, yet no approved treatments currently exist for this condition.
Novel Therapeutic Approach
STK-002 represents a targeted approach to addressing the root cause of ADOA (搜索). An estimated 65% to 90% of ADOA cases are caused by variants in the OPA1 (搜索) gene, most of which lead to haploinsufficiency resulting in 50% OPA1 protein expression and subsequent disease manifestation. The investigational therapy is designed to upregulate OPA1 protein expression by leveraging the non-mutant (wild-type) copy of the OPA1 gene to restore protein levels.
"ADOA (搜索) 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," explained Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics. "We are pleased to be expanding our approach into a new disease area, leveraging our learnings from Dravet syndrome (搜索) and applying them to the development of a potential disease-modifying medicine for people living with ADOA."
The therapy has already received orphan drug designation from the U.S. Food and Drug Administration (FDA) as a potential new treatment for ADOA (搜索), and Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-002.
Phase 1 Study Design and Objectives
The OSPREY study is a Phase 1, dose-escalating open-label study enrolling children and adults ages 6 to 55 who have an established diagnosis of ADOA (搜索) and confirmed disease-causing variants in the OPA1 (搜索) gene. The study's primary objectives focus on assessing the safety and tolerability of single ascending doses of STK-002, as well as determining drug exposure in blood.
Secondary objectives include evaluating changes in visual function, ocular structure, and quality of life following single doses of STK-002. The study follows a standard dose escalation design with participants enrolled into sequential cohorts receiving increasing dose levels of the investigational therapy.
Dose escalation of the first four cohorts is planned to continue through 2026 and early 2027, pending safety and tolerability assessments. The OSPREY study is actively recruiting in the United Kingdom and Germany, with additional European sites expected to activate in the coming months.
Broader Platform Implications
STK-002's development represents an expansion of Stoke Therapeutics' proprietary TANGO (Targeted Augmentation of Nuclear Gene Output) approach beyond neurological conditions. The company's lead program, zorevunersen for Dravet syndrome (搜索), has demonstrated potential for disease modification and is currently being evaluated in a Phase 3 study.
Stoke's initial focus targets diseases of the central nervous system and the eye caused by a loss of approximately 50% of normal protein levels (haploinsufficiency). The company reports that proof of concept has been demonstrated in other organs, tissues, and systems, supporting broad potential for their proprietary approach.
Dr. Yu-Wai-Man emphasized the significance of this development for the ADOA (搜索) community: "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."