AAV-mediated tyrosinase gene transfer restores melanogenesis and retinal function in a model of oculo-cutaneous albinism type I (OCA1).

Abstract

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.

• Authors: Annagiusi Gargiulo, Ciro Bonetti, Sandro Montefusco, Simona Neglia, Umberto Di Vicino, Elena Marrocco, Michele Della Corte, Luciano Domenici, Alberto Auricchio, Enrico M Surace
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 17 Issue 8 Pg. 1347-54 (Aug 2009) ISSN: 1525-0024 [Electronic] United States
• PMID: 19436266 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Melanins
• Monophenol Monooxygenase

Topics

• Albinism, Oculocutaneous (metabolism, pathology, therapy, ultrastructure)
• Animals
• Dependovirus (genetics)
• Electrophysiology
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Humans
• Iris (metabolism, pathology, ultrastructure)
• Melanins (metabolism)
• Melanocytes (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Microscopy, Electron
• Monophenol Monooxygenase (genetics, physiology)
• Retina (metabolism, pathology, ultrastructure)
• Retinal Pigment Epithelium (metabolism, pathology)