title: Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept.
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 MFRP mutations, 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 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene 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 rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Astra
authors.initials: A
authors.lastname: Dinculescu
authors.forename: Jackie
authors.initials: J
authors.lastname: Estreicher
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zenteno
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Wei Chieh
authors.initials: WC
authors.lastname: Huang
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Deng
authors.forename: Seok-Hong
authors.initials: SH
authors.lastname: Min
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: Andy
authors.initials: A
authors.lastname: Neeley
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Xinhua
authors.initials: X
authors.lastname: Shu
authors.forename: Margarita
authors.initials: M
authors.lastname: Matias-Florentino
authors.forename: Beatriz
authors.initials: B
authors.lastname: Buentello-Volante
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000628:therapy*; D000099274:Frizzled-Related Proteins
chemical_list: D005136:Eye Proteins; D008565:Membrane Proteins; C490110:MFRP protein, human; D000099274:Frizzled-Related Proteins; C423368:Mfrp protein, mouse