[HTML][HTML] Treatment potential for LCA5-associated leber congenital amaurosis

KE Uyhazi, P Aravand, BA Bell, Z Wei… - … & Visual Science, 2020 - iovs.arvojournals.org
KE Uyhazi, P Aravand, BA Bell, Z Wei, L Leo, LW Serrano, DJ Pearson, I Shpylchak, J Pham…
Investigative Ophthalmology & Visual Science, 2020iovs.arvojournals.org
Purpose: To determine the therapeutic window for gene augmentation for Leber congenital
amaurosis (LCA) associated with mutations in LCA5. Methods: Five patients (ages 6–31)
with LCA and biallelic LCA5 mutations underwent an ophthalmic examination including
optical coherence tomography (SD-OCT), full-field stimulus testing (FST), and pupillometry.
The time course of photoreceptor degeneration in the Lca5 gt/gt mouse model and the
efficacy of subretinal gene augmentation therapy with AAV8-hLCA5 delivered at postnatal …
Abstract
Purpose: To determine the therapeutic window for gene augmentation for Leber congenital amaurosis (LCA) associated with mutations in LCA5.
Methods: Five patients (ages 6–31) with LCA and biallelic LCA5 mutations underwent an ophthalmic examination including optical coherence tomography (SD-OCT), full-field stimulus testing (FST), and pupillometry. The time course of photoreceptor degeneration in the Lca5 gt/gt mouse model and the efficacy of subretinal gene augmentation therapy with AAV8-hLCA5 delivered at postnatal day 5 (P5)(early, n= 11 eyes), P15 (mid, n= 14), and P30 (late, n= 13) were assessed using SD-OCT, histologic study, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease.
Results: Patients with LCA5-LCA showed a maculopathy with detectable outer nuclear layer (ONL) in the pericentral retina and at least 4 log units of dark-adapted 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 nondetectable 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 was recapitulated in the Lca5 gt/gt mouse. Gene augmentation resulted 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 patients with LCA5-LCA, at a level equivalent to that observed in rescued Lca5 gt/gt mice, suggesting a window of opportunity for the treatment of patients with LCA5-LCA.
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