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
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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