Gene therapy for oculocutaneous albinism type 1

Abstract

Purpose : Oculocutaneous albinism type 1 (OCA1) results from autosomal recessive tyrosinase (TYR) mutations and is characterized by pigment deficiency within critical ocular support tissues, including the retinal pigment epithelium (RPE). OCA1 adversely affects retinal development, leading to foveal hypoplasia, nystagmus, and aberrant optic nerve fiber decussation. Patients with OCA1 face irreversible photosensitivity and low vision, making OCA1 therapies an unmet clinical need. OCA1 is well suited to benefit from adeno-associated virus (AAV) gene therapy given that one functional TYR copy is sufficient to prevent OCA1-related retinal disease and the RPE is accessible for gene delivery. We postulate that the extent of RPE pigmentation post-TYR delivery will correlate with improved functional outcomes. However, the optimal method for AAV-TYR delivery and the most effective promoter to drive exogenous TYR expression within the RPE remain unknown. Here, we compare three distinct methods of AAV-Tyr delivery (intravitreal, subretinal, and intravenous injections) and two constructs with varying RPE-specificity in OCA1 mice.

Methods : B6(Cg)-Tyr^c-2J/J mice, a well-studied OCA1 model, were used for this study. Each injection method was tested using both RPE-specific and ubiquitous constructs. Intravenous injections were performed at post-natal day 1, before the closure of the blood-retina barrier. Control mice received intravenous PBS. Subretinal injections were performed in one eye of 1-month-old mice; the opposite eye received subretinal PBS. Intravitreal injections were performed in one eye of 1-month-old mice; the opposite eye received intravitreal PBS. Pigmentation was qualitatively assessed through retinal images taken 4 weeks post-vector delivery and quantified through wholemount confocal imaging and histology.

Results : AAV-Tyr subretinal delivery resulted in pigmentation around the site of injection, whereas intravenous delivery of the same vectors resulted in widespread pigmentation throughout the RPE and choroid. Intravitreal injections did not result in pigmentation at the titer tested. Intravenously injected animals contained significantly greater pigment within the RPE compared to animals that received subretinal injection.

Conclusions : Intravenous AAV-Tyr delivery outperforms subretinal and intravitreal delivery methods in terms of the amount of pigment produced within the RPE of an OCA1 mouse model.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.