AAV-mediated tyrosinase gene transfer restores melanogenesis and retinal function in a model of oculo-cutaneous albinism type I (OCA1).
Oculo-cutaneous albinism type 1 (OCA1) is characterized by congenital hypopigmentation and is due to mutations in the TYROSINASE gene (TYR). In this study, we have characterized the morpho-functional consequences of the lack of tyrosinase activity in the spontaneous null mouse model of OCA1 (Tyr(c-2j)). Here, we show that adult Tyr(c-2j) mice have several retinal functional anomalies associated with photoreceptor loss. To test whether these anomalies are reversible upon TYR complementation, we performed intraocular administration of an adeno-associated virus (AAV)-based vector, encoding the human TYR gene, in adult Tyr(c-2j) mice. This resulted in melanosome biogenesis and ex novo synthesis of melanin in both neuroectodermally derived retinal pigment epithelium (RPE) and in neural crest-derived choroid and iris melanocytes. Ocular melanin accumulation prevented progressive photoreceptor degeneration and resulted in restoration of retinal function. Our results reveal novel properties of pigment cells and show that the developmental anomalies of albino mice are associated with defects occurring in postnatal life, adding novel insights on OCA1 disease pathogenesis. In addition, we provide proof-of-principle of an effective gene-based strategy relevant for future application in albino patients.
Gargiulo
Annagiusi
A
TIGEM, Telethon Institute of Genetics and Medicine, Napoli, Italy.
Bonetti
Ciro
C
Montefusco
Sandro
S
Neglia
Simona
S
Di Vicino
Umberto
U
Marrocco
Elena
E
Corte
Michele Della
MD
Domenici
Luciano
L
Auricchio
Alberto
A
Surace
Enrico M
EM
D016115:Albinism, Oculocutaneous / Q000378:metabolism* / Q000473:pathology / Q000628:therapy* / Q000648:ultrastructure; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004594:Electrophysiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007498:Iris / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology
D008543:Melanins; D014442:Monophenol Monooxygenase