Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model.

ABSTRACT

Defects in aryl hydrocarbon receptor interacting protein-like1 (AIPL1) are associated with blinding diseases with a wide range of severity in humans. We examined the mechanism behind autosomal dominant cone-rod dystrophy (adCORD) caused by 12 base pair (bp) deletion at proline 351 of hAIPL1 (P351Δ12) mutation in the primate-specific region of human AIPL1. Mutant P351Δ12 human isoform, aryl hydrocarbon receptor interacting protein-like 1 (hAIPL1) mice demonstrated a CORD phenotype with early defects in cone-mediated vision and subsequent photoreceptor degeneration. A dominant CORD phenotype was observed in double transgenic animals expressing both mutant P351Δ12 and normal hAIPL1, but not with co-expression of P351Δ12 hAIPL1 and the mouse isoform, aryl hydrocarbon receptor interacting protein-like 1 (mAipl1). Despite a dominant effect of the mutation, we successfully rescued cone-mediated vision in P351Δ12 hAIPL1 mice following high over-expression of WT hAIPL1 by adeno-associated virus-mediated gene delivery, which was stable up to 6 months after treatment. Our transgenic P351Δ12 hAIPL1 mouse offers a novel model of AIPL1-CORD, with distinct defects from both the Aipl1-null mouse mimicking LCA and the Aipl1-hypomorphic mice mimicking a slow progressing RP.