Files and links (1)
Published, Version of Record (VoR)Open Access (License Unspecified), Open
Journal article
Gene Therapy Fully Restores Vision to the All-Cone Nrl(-/-) Gucy2e(-/-) Mouse Model of Leber Congenital Amaurosis-1
Human gene therapy, v 26(9), pp 575-592
01 Sep 2015
PMID: 26247368
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mutations in GUCY2D are the cause of Leber congenital amaurosis type 1 (LCA1). GUCY2D encodes retinal guanylate cyclase-1 (retGC1), a protein expressed exclusively in outer segments of photoreceptors and essential for timely recovery from photoexcitation. Recent clinical data show that, despite a high degree of visual disturbance stemming from a loss of cone function, LCA1 patients retain normal photoreceptor architecture, except for foveal cone outer segment abnormalities and, in some patients, foveal cone loss. These results point to the cone-rich central retina as a target for GUCY2D replacement. LCA1 gene replacement studies thus far have been conducted in rod-dominant models (mouse) or with vectors and organisms lacking clinical translatability. Here we investigate gene replacement in the Nrl(-/-) Gucy2e(-/-) mouse, an all-cone model deficient in retGC1. We show that AAV-retGC1 treatment fully restores cone function, cone-mediated visual behavior, and guanylate cyclase activity, and preserves cones in treated Nrl(-/-) Gucy2e(-/-) mice over the long-term. A novel finding was that retinal function could be restored to levels above that in Nrl(-/-) controls, contrasting results in other models of retGC1 deficiency. We attribute this to increased cyclase activity in treated Nrl(-/-) Gucy2e(-/-) mice relative to Nrl(-/-) controls. Thus, Nrl(-/-) Gucy2e(-/-) mice possess an expanded dynamic range in ERG response to gene replacement relative to other models. Lastly, we show that a candidate clinical vector, AAV5-GRK1-GUCY2D, when delivered to adult Nrl(-/-) Gucy2e(-/-) mice, restores retinal function that persists for at least 6 months. Our results provide strong support for clinical application of a gene therapy targeted to the cone-rich, central retina of LCA1 patients.
Metrics
Details
- Title
- Gene Therapy Fully Restores Vision to the All-Cone Nrl(-/-) Gucy2e(-/-) Mouse Model of Leber Congenital Amaurosis-1
- Creators
- Sanford L Boye - University of FloridaJames J Peterson - 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, FloridaShreyasi Choudhury - University of FloridaSeok Hong Min - University of FloridaQing Ruan - University of FloridaK Tyler McCullough - University of FloridaZhonghong Zhang - University of FloridaElena V Olshevskaya - Salus UniversityIgor V Peshenko - Salus UniversityWilliam W Hauswirth - University of FloridaXi-Qin Ding - University of OklahomaAlexander M Dizhoor - Salus UniversityShannon E Boye - 1 Department of Ophthalmology, College of Medicine, University of Florida , Gainesville, Florida
- Publication Details
- Human gene therapy, v 26(9), pp 575-592
- Publisher
- Mary Ann Liebert
- Grant note
- R01EY11522 / NEI NIH HHS R01EY019490 / NEI NIH HHS P30EY021721 / NEI NIH HHS R01 EY011522 / NEI NIH HHS R01EY024280 / NEI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000360966700002
- Scopus ID
- 2-s2.0-84941275655
- Other Identifier
- 991022035111504721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental