AAV-mediated Tyrosinase Gene Transfer Restores Melanogenesis and Retinal Function in a Model of Oculo-cutaneous Albinism Type I (OCA1)
AAV-mediated Tyrosinase Gene Transfer Restores Melanogenesis and Retinal Function in a Model of Oculo-cutaneous Albinism Type I (OCA1)
复制标题
DOI：
10.1038/mt.2009.112
复制
发表时间：
2009-08-01
影响因子：
12.4
通讯作者：
Surace, Enrico M.
中科院分区：
文献类型：
--
作者：
Gargiulo, Annagiusi;Bonetti, Ciro;Surace, Enrico M.
眼皮肤白化病1型（OCA 1）的特征是先天性色素减退，是由于酪氨酸酶基因（TYR）突变。在这项研究中，我们的特点是缺乏酪氨酸酶活性的OCA 1（酪氨酸（c-2 j））的自发无效小鼠模型的形态功能的后果。在这里，我们表明，成年Tyr（c-2 j）小鼠有几个视网膜功能异常与感光细胞的损失。为了测试这些异常在TYR互补后是否是可逆的，我们在成年Tyr（c-2 j）小鼠中进行了基于腺相关病毒（AAV）的载体的眼内施用，所述载体编码人TYR基因。这导致黑素体生物发生和神经外胚层来源的视网膜色素上皮（RPE）和神经嵴来源的脉络膜和虹膜黑素细胞中的黑素从头合成。眼黑色素的积累阻止了进行性感光细胞变性，并导致视网膜功能的恢复。我们的研究结果揭示了色素细胞的新特性，并表明白化病小鼠的发育异常与出生后生活中发生的缺陷有关，增加了对OCA 1疾病发病机制的新见解。此外，我们提供了一个有效的基因为基础的战略相关的白化病患者的未来应用的原则证明。
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.