Treatment Potential for LCA5-Associated Leber Congenital Amaurosis
Autor: | Ivan Shpylchak, Vidyullatha Vasireddy, Katherine E. Uyhazi, Denise J. Pearson, Zhangyong Wei, Jean Bennett, Lanfranco Leo, Leona W. Serrano, Puya Aravand, Tomas S. Aleman, Brent A. Bell, Jennifer Pham |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Retinal degeneration Male genetic structures Leber Congenital Amaurosis Visual Acuity Mice 0302 clinical medicine lebercilin Child LCA5 medicine.diagnostic_test Optical Imaging Dependovirus gene therapy medicine.anatomical_structure Phenotype Female AAV8 Erg Microtubule-Associated Proteins Pupillometry Tomography Optical Coherence Adult medicine.medical_specialty Genetic Vectors Retina 03 medical and health sciences Young Adult Ophthalmology medicine Electroretinography Animals Humans Outer nuclear layer Eye Proteins business.industry Pupil Genetic Therapy medicine.disease eye diseases Tissue Degeneration Mice Inbred C57BL Disease Models Animal 030104 developmental biology 030221 ophthalmology & optometry Maculopathy Visual Field Tests sense organs Visual Fields business |
Zdroj: | Investigative Ophthalmology & Visual Science |
ISSN: | 1552-5783 0146-0404 |
Popis: | 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 Lca5gt/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 Lca5gt/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 Lca5gt/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 Lca5gt/gt mouse. Gene augmentation resulted in structural and functional rescue in the Lca5gt/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 Lca5gt/gt mice, suggesting a window of opportunity for the treatment of patients with LCA5-LCA. |
Databáze: | OpenAIRE |
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