Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis.
X-linked juvenile retinoschisis (RS) is a common cause of juvenile macular degeneration in males. RS is characterized by cystic spoke-wheel-like maculopathy, peripheral schisis, and a negative (b-wave more reduced than a-wave) electroretinogram (ERG). These symptoms are due to mutations in the RS1 gene in Xp22.2 leading to loss of functional protein. No medical treatment is currently available. We show here that in an Rs1h-deficient mouse model of human RS, delivery of the human RS1 cDNA with an AAV vector restored expression of retinoschisin to both photoreceptors and the inner retina essentially identical to that seen in wild-type mice. More importantly, unlike an earlier study with a different AAV vector and promoter, this work shows for the first time that therapeutic gene delivery using a highly specific AAV5-opsin promoter vector leads to progressive and significant improvement in both retinal function (ERG) and morphology, with preservation of photoreceptor cells that, without treatment, progressively degenerate.
Min
Seok H
SH
Department of Ophthalmology, University of Florida College of Medicine, Gainesville, 32610, USA. smin@eye.ufl.edu
Molday
Laurie L
LL
Seeliger
Mathias W
MW
Dinculescu
Astra
A
Timmers
Adrian M
AM
Janssen
Andreas
A
Tonagel
Felix
F
Tanimoto
Naoyuki
N
Weber
Bernhard H F
BH
Molday
Robert S
RS
Hauswirth
William W
WW
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D008040:Genetic Linkage; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000473:pathology / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000235:genetics*; D041441:Retinoschisis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D014162:Transfection
D015815:Cell Adhesion Molecules; D005136:Eye Proteins; C108726:RS1 protein, human; C491843:RS1 protein, mouse