發佈日期：2012/01/19 am08:57:09

內容：
Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of
degenerations of the retina, can be due to mutations in the MFRP (membrane-type
frizzled-related protein) gene. An RP patient with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized with non-invasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy.Proof-of-concept studies were performed in the rd6 Mfrp-mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin (smCBA) promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery at postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the RPE (retinal pigment epithelium) apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.
中文概要簡述:
視網膜色素病變是一種視網膜退化的疾病，若由於MFRP突變所造成的，患有因MFRP突變所引起的RP的病人，其首項基因接合處突變，描述了非侵入性視網膜與視覺上的研究。儘管複雜，但仍顯示出視網膜退化也許可適用於基因療法。 概念性驗證的研究已經在rd6 Mfrp突變的老鼠上實驗過了，速效的酚基乙氨酸衣殼突變AAV8(Y733F)傳染媒介包括了小雞BETA肌動蛋白(smCBA)促進了野生老鼠MFRP基因的使用，視網膜下方的傳染媒介在出生後14天開始傳送以預防視網膜衰退。治療法拯救了桿狀及錐狀的光感應器，由視網膜電圖顯示及視網膜組織學在2歲大時所估計而得。此傳導AAV基因也導致了強勁顯著的MFRP表示是在其一般位置，也就是位於人類視網膜色素細胞頂端的膜以及微絨毛之間。MFRP-RP和我們的初步數據表示，對於在rd6老鼠上所得到的基因療法的反應，證明了此種RP的形式是一個基因療法的潛在目標。