CLN2 Batten disease is a lysosomal disease caused by biallelic mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). Insufficient TPP1 enzyme causes accumulation of lysosomal storage material resulting in progressive neurological and retinal degeneration leading to blindness. A human recombinant form of this enzyme, cerliponase alfa, is approved to slow the loss of ambulation in children with CLN2 disease, although intracerebroventricular (ICV) delivery has been shown not to affect the ocular manifestations of the disease. CLN2 natural history data demonstrate symmetrical bilateral onset and progression of photoreceptor degeneration in a predictable pattern. TTX-381 is an investigational one-time gene therapy comprised of a recombinant AAV9 vector that delivers a human CLN2 transgene directly to the retina during a single administration procedure and is designed to induce sustained secretion of TPP1 to prevent progressive photoreceptor degeneration. Here, we report 1-year data for the first 6 participants of the first-in-human clinical trial of subretinal TTX-381. TTX-381 continues to be well tolerated with a favorable safety profile. Dose-related TPP1 expression, measured in aqueous humor, was observed in all treated eyes by Day 30. At 1 year, SD-OCT demonstrated no progression of photoreceptor loss in the treated eyes of 5 of 6 participants, including several treated eyes with reversal of photoreceptor loss compared with baseline. In contrast, progressive retinal degeneration was observed in 5 of 6 untreated eyes, resulting in unequivocal differences between treated and untreated eyes of the same participant at 1 year. One participant had too little photoreceptor degeneration in either eye over the 1-year study period to determine change from baseline or inter-eye difference. Collectively, these data were used to select the dose level for an expansion cohort in the ongoing trial to further characterize the safety and efficacy profiles of TTX-381.