Journal article
AAV2/4-RS1 gene therapy in the retinoschisin knockout mouse model of X-linked retinoschisis
PloS one, Vol.17(12), p.e0276298
2022
DOI: 10.1371/journal.pone.0276298
PMCID: PMC9728878
PMID: 36477475
Abstract
To evaluate efficacy of a novel adeno-associated virus (AAV) vector, AAV2/4-RS1, for retinal rescue in the retinoschisin knockout (Rs1-KO) mouse model of X-linked retinoschisis (XLRS). Brinzolamide (Azopt®), a carbonic anhydrase inhibitor, was tested for its ability to potentiate the effects of AAV2/4-RS1.
AAV2/4-RS1 with a cytomegalovirus (CMV) promoter (2x1012 viral genomes/mL) was delivered to Rs1-KO mice via intravitreal (N = 5; 1μL) or subretinal (N = 21; 2μL) injections at postnatal day 60-90. Eleven mice treated with subretinal therapy also received topical Azopt® twice a day. Serial full field electroretinography (ERG) was performed starting at day 50-60 post-injection. Mice were evaluated using a visually guided swim assay (VGSA) in light and dark conditions. The experimental groups were compared to untreated Rs1-KO (N = 11), wild-type (N = 12), and Rs1-KO mice receiving only Azopt® (N = 5). Immunofluorescence staining was performed to assess RS1 protein expression following treatment.
The ERG b/a ratio was significantly higher in the subretinal plus Azopt® (p<0.0001), subretinal without Azopt® (p = 0.0002), and intravitreal (p = 0.01) treated eyes compared to untreated eyes. There was a highly significant subretinal treatment effect on ERG amplitudes collectively at 7-9 months post-injection (p = 0.0003). Cones showed more effect than rods. The subretinal group showed improved time to platform in the dark VGSA compared to untreated mice (p<0.0001). RS1 protein expression was detected in the outer retina in subretinal treated mice and in the inner retina in intravitreal treated mice.
AAV2/4-RS1 shows promise for improving retinal phenotype in the Rs1-KO mouse model. Subretinal delivery was superior to intravitreal. Topical brinzolamide did not improve efficacy. AAV2/4-RS1 may be considered as a potential treatment for XLRS patients.
Details
- Title: Subtitle
- AAV2/4-RS1 gene therapy in the retinoschisin knockout mouse model of X-linked retinoschisis
- Creators
- Brittni A Scruggs - University of IowaSajag Bhattarai - University of IowaMegan Helms - University of IowaIoana Cherascu - University of Iowa Institute for Vision Research and the Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United States of AmericaAdisa Salesevic - University of Iowa Institute for Vision Research and the Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United States of AmericaElliot Stalter - Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of AmericaJoseph Laird - University of IowaSheila A Baker - University of IowaArlene V Drack - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.17(12), p.e0276298
- DOI
- 10.1371/journal.pone.0276298
- PMID
- 36477475
- PMCID
- PMC9728878
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Grant note
- name: Chakraborty Family Foundation; DOI: 10.13039/100001818, name: Research to Prevent Blindness; DOI: 10.13039/100000053, name: National Eye Institute, award: P30 EY025580
- Language
- English
- Date published
- 2022
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; University College Courses; Ophthalmology and Visual Sciences
- Record Identifier
- 9984327159802771
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