Targeting the OPA1 pathway in autosomal dominant optic atrophy (ADOA): 25 years from gene discovery to therapeutic strategy

INTRODUCTION: Autosomal Dominant Optic Atrophy (ADOA) is a rare hereditary optic neuropathy primarily caused by OPA1 mutations. Retinal ganglion cell (RGC) loss results in variable visual impairments, occasionally accompanied by extra-ocular manifestations. ADOA also involves a developmental component consistent with OPA1's essential role in mitochondrial fusion, cristae organization, and quality control. As such, ADOA serves as a paradigm for studying mitochondrial contributions to neurodegeneration. AREAS COVERED: This article provides a comprehensive overview of ADOA, covering genetic and clinical aspects while distinguishing between degenerative and developmental features of the pathology. The author examines OPA1 function and assesses emerging therapeutic strategies - ranging from gene augmentation and small-molecule therapeutics to alternative targets - before appraising translational challenges. EXPERT OPINION: Antisense therapies targeting OPA1 haploinsufficiency are among the more advanced ADOA treatments currently under human safety evaluation, with other modalities following closely in development. However, the field still lacks robust clinical endpoints for the highly variable and slowly progressive phenotype. Furthermore, developmental RGC loss may limit therapeutic efficacy of late-stage interventions - a challenge compounded by the difficulty of early diagnosis. Nevertheless, the FDA's recent shift toward Bayesian statistical frameworks and the emergence of neuroprotective alternative targets are expected to streamline the clinical development for ADOA.