From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity

The identification of somatic drivers has turned a field once based on morphology into a set of molecular pathways that can potentially be targeted with drugs. Vascular lesions of the eye and ocular adnexa used to be classified by their appearance; many of them are now defined by a post-zygotic variant in a signaling cascade for which an inhibitor is already available. This review groups these lesions by signaling axis and examines how close each pathway is to clinical application. Belzutifan seems to be the most advanced. In a single-arm phase 2 subgroup with prospectively graded retinal endpoints, HIF-2α inhibition improved all 16 evaluable eyes in 12 participants, without a comparator arm. PI3K and mTOR inhibition is supported by clinical studies in predominantly non-ocular venous and lymphatic malformations, with more consistent evidence for symptomatic benefit than for volume reduction. Direct orbital evidence remains limited to small series. MEK inhibition treats RAS-driven disease in other locations, but it can also cause a retinopathy of its own, which makes it both a therapy and an ophthalmic concern. Gq/11 signaling accounts for most capillary malformations, Sturge–Weber syndrome and both choroidal hemangiomas, which are separated by the mutated codon rather than by histology, and it remains a preclinical target. Junctional GJA4 signaling defines the orbital cavernous venous malformation, probably the clearest example of a disease defined by its driver. Genotyping of ocular lesions is limited by tissue access and by variant allele frequencies that are commonly missed by standard panels.