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Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa
- Publication Year :
- 2012
- Publisher :
- Oxford University Press, 2012.
-
Abstract
- Approximately 36 000 cases of simplex and familial retinitis pigmentosa (RP) worldwide are caused by a loss in phosphodiesterase (PDE6) function. In the preclinical Pde6α(nmf363) mouse model of this disease, defects in the α-subunit of PDE6 result in a progressive loss of photoreceptors and neuronal function. We hypothesized that increasing PDE6α levels using an AAV2/8 gene therapy vector could improve photoreceptor survival and retinal function. We utilized a vector with the cell-type-specific rhodopsin (RHO) promoter: AAV2/8(Y733F)-Rho-Pde6α, to transduce Pde6α(nmf363) retinas and monitored its effects over a 6-month period (a quarter of the mouse lifespan). We found that a single injection enhanced survival of photoreceptors and improved retinal function. At 6 months of age, the treated eyes retained photoreceptor cell bodies, while there were no detectable photoreceptors remaining in the untreated eyes. More importantly, the treated eyes demonstrated functional visual responses even after the untreated eyes had lost all vision. Despite focal rescue of the retinal structure adjacent to the injection site, global functional rescue of the entire retina was observed. These results suggest that RP due to PDE6α deficiency in humans, in addition to PDE6β deficiency, is also likely to be treatable by gene therapy.
- Subjects :
- medicine.medical_specialty
Rhodopsin
genetic structures
Genetic enhancement
Period (gene)
Genetic Vectors
Immunoblotting
Mice, Transgenic
Photoreceptor cell
Retina
Mice
PDE6B
Transduction, Genetic
Ophthalmology
Retinitis pigmentosa
Genetics
medicine
Electroretinography
Animals
Promoter Regions, Genetic
Molecular Biology
Genetics (clinical)
Cyclic Nucleotide Phosphodiesterases, Type 6
biology
medicine.diagnostic_test
General Medicine
Articles
Genetic Therapy
Dependovirus
medicine.disease
eye diseases
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
biology.protein
sense organs
Retinitis Pigmentosa
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....6b1e65405cf19d04213f22f5f1bcf9ce