title: Gene therapy into photoreceptors and Müller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models.
abstract: Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encoding an enzyme or channel protein, and targeting expression to one cell type. Therapy for the human CRB1 disease will be more complex, as CRB1 is a structural and signaling transmembrane protein present in three cell classes: Müller glia, cone and rod photoreceptors. In this study, we applied CRB1 and CRB2 gene therapy vectors in Crb1-retinitis pigmentosa mouse models at mid-stage disease. We tested if CRB expression restricted to Müller glial cells or photoreceptors or co-expression in both is required to recover retinal function. We show that targeting both Müller glial cells and photoreceptors with CRB2 ameliorated retinal function and structure in Crb1 mouse models. Surprisingly, targeting a single cell type or all cell types with CRB1 reduced retinal function. We show here the first pre-clinical studies for CRB1-related eye disorders using CRB2 vectors and initial elucidation of the cellular mechanisms underlying CRB1 function.
authors.affiliation: Department of Neuromedical Genetics.
authors.forename: Lucie P
authors.initials: LP
authors.lastname: Pellissier
authors.affiliation: Department of Neuromedical Genetics.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Quinn
authors.affiliation: Department of Neuromedical Genetics.
authors.forename: C Henrique
authors.initials: CH
authors.lastname: Alves
authors.affiliation: Department of Neuromedical Genetics.
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Vos
authors.affiliation: Department of Retinal Signal Processing and.
authors.forename: Jan
authors.initials: J
authors.lastname: Klooster
authors.affiliation: Department of Molecular and Cellular Biology, The Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA and.
authors.forename: John G
authors.initials: JG
authors.lastname: Flannery
authors.affiliation: Department of Cortical Structure & Function, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands.
authors.forename: J Alexander
authors.initials: JA
authors.lastname: Heimel
authors.affiliation: Department of Neuromedical Genetics Department of Ophthalmology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands j.wijnholds@nin.knaw.nl.
authors.forename: Jan
authors.initials: J
authors.lastname: Wijnholds
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000502:physiology*; D015316:Genetic Therapy; D057809:HEK293 Cells; D006801:Humans; D058449:Intravitreal Injections; D008565:Membrane Proteins / Q000235:genetics; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012160:Retina / Q000473:pathology / Q000503:physiopathology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000628:therapy
chemical_list: C492531:CRB2 protein, human; D002352:Carrier Proteins; C453730:Crb1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins