Treatment Potential for LCA5-associated Leber Congenital Amaurosis

Abstract

Purpose : To determine the therapeutic window for gene replacement in inherited retinal degenerations caused by mutations in the gene encoding Lebercilin (LCA5).

Methods : Five patients (ages 6-31) with Leber congenital amaurosis (LCA) and biallelic LCA5 mutations underwent a complete ophthalmic exam including spectral domain optical coherence tomography (SD-OCT), full-field stimulus testing (FST) and pupillometry. In the Lca5^gt/gt mouse model of the disease, the time course of photoreceptor degeneration and the efficacy of subretinal gene replacement therapy with AAV8-hLCA5 administered in early (P5), mid (P15), and late (P30) stage disease were assessed using SD-OCT, histology, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease.

Results : Patients with LCA5 mutations have a maculopathy with detectable outer nuclear layer (ONL) in the pericentral retina and ~4 log units of sensitivity loss. The Lca5^gt/gt mouse has a similarly severe and rapid photoreceptor degeneration. The ONL became progressively thinner and was undetectable by P60. Rod- and cone-mediated ERGs were severely reduced in amplitudes at P30 and became non-detectable by P60. Subretinal AAV8-hLCA5 administered to Lca5^gt/gt mice at P5 and P15, but not at P30, resulted in structural and functional rescue.

Conclusions : LCA5-LCA is a particularly severe form of LCA that is recapitulated in the Lca5^gt/gt mouse. Gene replacement results in structural and functional rescue in the Lca5^gt/gt mouse if delivered before P30. Retained photoreceptors were visible within the central retina in all LCA5-LCA patients, in most at a level equivalent to that observed in rescued Lca5^gt/gt mice, suggesting a window of opportunity for the treatment of LCA5-LCA patients.

This is a 2020 ARVO Annual Meeting abstract.