Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness

Academic Article


  • Most genetically distinct inherited retinal degenerations are primary photoreceptor degenerations. We selected a severe early onset form of Leber congenital amaurosis (LCA), caused by mutations in the gene LCA5, in order to test the efficacy of gene augmentation therapy for a ciliopathy. The LCA5-encoded protein, Lebercilin, is essential for the trafficking of proteins and vesicles to the photoreceptor outer segment. Using the AAV serotype AAV7m8 to deliver a human LCA5 cDNA into an Lca5 null mouse model of LCA5, we show partial rescue of retinal structure and visual function. Specifically, we observed restoration of rod-and-cone-driven electroretinograms in about 25% of injected eyes, restoration of pupillary light responses in the majority of treated eyes, an ∼20-fold decrease in target luminance necessary for visually guided behavior, and improved retinal architecture following gene transfer. Using LCA5 patient-derived iPSC-RPEs, we show that delivery of the LCA5 cDNA restores lebercilin protein and rescues cilia quantity. The results presented in this study support a path forward aiming to develop safety and efficacy trials for gene augmentation therapy in human subjects with LCA5 mutations. They also provide the framework for measuring the effects of intervention in ciliopathies and other severe, early-onset blinding conditions. LCA5 mutations cause a ciliopathy manifest as severe, congenital blindness. In this issue of Molecular Therapy, Bennett et al. used AAV7m8 to demonstrate partial rescue of retinal structure and visual function in an Lca5 null mouse and rescue of cilia in LCA5 patient-derived stem cell models.
  • Authors

    Published In

  • Molecular Therapy  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 17426653
  • Author List

  • Song JY; Aravand P; Nikonov S; Leo L; Lyubarsky A; Bennicelli JL; Pan J; Wei Z; Shpylchak I; Herrera P
  • Start Page

  • 1581
  • End Page

  • 1593
  • Volume

  • 26
  • Issue

  • 6