학술논문
Gene Therapy for Retinitis Pigmentosa Caused by MFRPMutations: Human Phenotype and Preliminary Proof of Concept.
Document Type
Article
Author
Dinculescu, Astra; Estreicher, Jackie; Zenteno, Juan C.; Aleman, Tomas S.; Schwartz, Sharon B.; Huang, Wei Chieh; Roman, Alejandro J.; Sumaroka, Alexander; Li, Qiuhong; Deng, Wen-Tao; Min, Seok-Hong; Chiodo, Vince A.; Neeley, Andy; Liu, Xuan; Shu, Xinhua; Matias-Florentino, Margarita; Buentello-Volante, Beatriz; Boye, Sanford L.; Cideciyan, Artur V.; Hauswirth, William W.
Source
Subject
*GENE therapy
*RETINITIS pigmentosa
*GENETIC mutation
*PHENOTYPES
*RETINAL degeneration
*MEMBRANE proteins
*GENETICS
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Language
ISSN
1043-0342
Abstract
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. A patient with RP with MFRPmutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive 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 Mfrpmutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrpgene was used. Subretinal vector delivery on 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 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 rd6mouse suggest that this form of RP is a potential target for gene-based therapy. [ABSTRACT FROM AUTHOR]