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A. Gargiulo, S. Montefusco, C. Bonetti, S. Neglia, E. M. Surace; Morphological and Functional Recovery of Tyrosinase Albino Retinal Anomalies by Adeno-Associated Viral Vector Treatment. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5358.
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© ARVO (1962-2015); The Authors (2016-present)
Oculocutaneous Albinism type 1 (OCA1) is an autosomal recessive disorder due to mutations in the tyrosinase gene (TYR), an essential enzyme for melanin biosynthesis in both melanocytes and RPE (Retinal Pigment Epithelium) of the retina. Mutations in TYR protein leads to the lack or the decreased melanin synthesis resulting in congenital hypopigmentation and developmental abnormalities including foveal hypoplasia and abnormal targeting of the optic nerve projections to the brain. These anomalies result in nystagmus, strabismus, reduced visual acuity and loss of binocular vision. We recently determined that beside the congenital anomalies associated to TYR mutations, mice harbouring a lack of function mutation in TYR gene (Tyrc-2j) show a progressive loss of retinal functions as assessed by ERG (electroretinogram) and recovery from retinal desensitization analysis. Moreover, these retinal dysfunctions are associated to photoreceptor loss. In this study we sought whether morphological and functional anomalies present in Tyrc-2j mice are reversible following postnatal AAV mediated gene transfer of the human TYR gene to the retina.
In order to correct the electrophysiological anomalies and the pigmentation defect present in Tyrc-2j mice, we performed subretinal injections of Adeno-Associated Viral Vectors (AAV) harbouring the human TYR gene, AAV2/1-CMV-hTYR, in one month old mice. Assessment of retinal functional and morphological recovery was performed 2 and 7 months post injections by electrophysiology and histological analysis.
AAV2/1-mediated delivery of human TYR gene resulted in melanin synthesis in the RPE trasduced area. This was observed regardless of the timing of vector delivery (P0, P30, P180). ERG and recovery of photoreceptor function desensitization analysis showed significant improvements either after 2 or 7 months post treatment. Histological analysis demonstrates protection from photoreceptor degeneration.
Subretinal injection of AAV2/1-CMV-hTYR in adult retina results in de-novo synthesis of melanin in the RPE and protects from progressive photoreceptors degeneration, suggesting possible future application in human patients.
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