Ocular gene therapy as a sustained drug delivery system: pharmacokinetic and genokinetic perspectives

Ocular pharmacotherapy is constrained by compartmental anatomy and clearance barriers that limit sustained posterior-segment exposure. Intravitreal bolus dosing, therefore, remains dominant for retinal disease but produces peak-trough profiles and frequent retreatment. Long-acting implants and refillable systems can prolong exposure, yet are finite or maintenance-dependent. Ocular gene therapy introduces a different paradigm in which transduced retinal cells act as localized 'biofactories,' enabling prolonged intraocular production of therapeutic proteins after a single or infrequent administration. This review integrates pharmacokinetic principles with determinants of transgene expression, including vector/capsid design, promoter architecture, route-dependent biodistribution (subretinal, intravitreal, suprachoroidal), and immune modulation, to explain typical kinetics (lag phase, rise to plateau, and potential attenuation). We highlight an infusion-equivalent modeling framework that treats transgene-driven protein output as sustained input balanced by first-order loss, providing parameters for time to plateau, steady-state exposure, and variability. Finally, we discuss translational implications for efficacy and safety, including exposure-response and therapeutic window definition in emerging retinal gene therapy programs (notably anti-VEGF), and future directions such as tunable expression systems and biomarker-linked, model-informed dose optimization.