Gene therapy into photoreceptors and Müller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models

Hum Mol Genet. 2015 Jun 1;24(11):3104-18. doi: 10.1093/hmg/ddv062. Epub 2015 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Disease Models, Animal
  • Ependymoglial Cells / physiology*
  • Genetic Therapy
  • HEK293 Cells
  • Humans
  • Intravitreal Injections
  • Membrane Proteins / genetics
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / genetics*
  • Retina / pathology
  • Retina / physiopathology
  • Retinal Cone Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / therapy


  • CRB2 protein, human
  • Carrier Proteins
  • Crb1 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins