biostudies-literatureBuck TMAlgemene Nederlandse Vereniging ter voorkoming van BlindheidStichting Blinden-PenningLandelijke Stichting voor Blinden en SlechtziendenStichting Steunfonds UitzichtFoundation Fighting BlindnessRotterdamse Stichting BlindenbelangenStichting MaculaFondsZonMwStichting Blindenhulp423-441https://www.ebi.ac.uk/biostudies/studies/S-EPMC7848734biostudies-literatureUnknown20Loss of Crumbs homolog 1 (CRB1) or CRB2 proteins in Müller cells or photoreceptors in the mouse retina results in a CRB dose-dependent retinal phenotype. In this study, we present a novel Müller cell-specific Crb1 KO Crb2 LowMGC retinitis pigmentosa mouse model (complete loss of CRB1 and reduced levels of CRB2 specifically in Müller cells). The Crb double mutant mice showed deficits in electroretinography, optokinetic head tracking, and retinal morphology. Exposure of retinas to low levels of dl-α-aminoadipate acid induced gliosis and retinal disorganization in Crb1 KO Crb2 LowMGC retinas but not in wild-type or Crb1-deficient retinas. Crb1 KO Crb2 LowMGC mice showed a substantial decrease in inner/outer photoreceptor segment length and optokinetic head-tracking response. Intravitreal application of rAAV vectors expressing human CRB2 (hCRB2) in Müller cells of Crb1 KO Crb2 LowMGC mice subsequently exposed to low levels of dl-α-aminoadipate acid prevented loss of vision, whereas recombinant adeno-associated viral (rAAV) vectors expressing human CRB1 (hCRB1) did not. Both rAAV vectors partially protected the morphology of the retina. The results suggest that hCRB expression in Müller cells is vital for control of retinal cell adhesion at the outer limiting membrane, and that the rAAV-cytomegalovirus (CMV)-hCRB2 vector is more potent than rAAV-minimal CMV (CMVmin)-hCRB1 in protection against loss of vision.Molecular therapy. Methods & clinical developmentAAV-CRB2 protects against vision loss in an inducible CRB1 retinitis pigmentosa mouse model.PMC784873443200004Vos RMAlves CHBuck TMWijnholds JfalseAAV-CRB2 protects against vision loss in an inducible CRB1 retinitis pigmentosa mouse model.Loss of Crumbs homolog 1 (CRB1) or CRB2 proteins in Müller cells or photoreceptors in the mouse retina results in a CRB dose-dependent retinal phenotype. In this study, we present a novel Müller cell-specific Crb1 KO Crb2 LowMGC retinitis pigmentosa mouse model (complete loss of CRB1 and reduced levels of CRB2 specifically in Müller cells). The Crb double mutant mice showed deficits in electroretinography, optokinetic head tracking, and retinal morphology. Exposure of retinas to low levels of dl-α-aminoadipate acid induced gliosis and retinal disorganization in Crb1 KO Crb2 LowMGC retinas but not in wild-type or Crb1-deficient retinas. Crb1 KO Crb2 LowMGC mice showed a substantial decrease in inner/outer photoreceptor segment length and optokinetic head-tracking response. Intravitreal application of rAAV vectors expressing human CRB2 (hCRB2) in Müller cells of Crb1 KO Crb2 LowMGC mice subsequently exposed to low levels of dl-α-aminoadipate acid prevented loss of vision, whereas recombinant adeno-associated viral (rAAV) vectors expressing human CRB1 (hCRB1) did not. Both rAAV vectors partially protected the morphology of the retina. The results suggest that hCRB expression in Müller cells is vital for control of retinal cell adhesion at the outer limiting membrane, and that the rAAV-cytomegalovirus (CMV)-hCRB2 vector is more potent than rAAV-minimal CMV (CMVmin)-hCRB1 in protection against loss of vision.2021-01-01T00:00:00Z2021 Mar2024-11-13T07:56:20.126Z2021-02-21T10:03:49ZS-EPMC78487343357543410.1016/j.omtm.2020.12.012