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Mutations in the gene for Retinitis Pigmentosa GTPase Regulator ( RPGR ) cause the X-linked form of inherited retinal degeneration, and the majority are frameshift mutations in a highly repetitive, purine-rich region of  RPGR  known as the OFR15 exon. Truncation of the reading frame in this terminal exon ablates the functionally important C-terminal domain. We hypothesized that targeted excision in ORF15 by CRISPR/Cas9 and the ensuing repair by non-homologous end joining could restore  RPGR  reading frame in a portion of mutant photoreceptors thereby correcting gene function in vivo. We tested this hypothesis in the  rd9  mouse, a naturally occurring mutant line that carries a frameshift mutation in  RPGR  ORF15 , through a combination of germline and somatic gene therapy approaches. In germline gene-edited  rd9  mice, probing with RPGR domain-specific antibodies demonstrated expression of full length RPGR ORF15  protein. Hallmark features of RPGR mutation-associated early disease phenotypes, such as mislocalization of cone opsins, were no longer present. Subretinal injections of the same guide RNA (sgRNA) carried in AAV sgRNA and SpCas9 expression vectors restored reading frame of  RPGR  ORF15  in a subpopulation of cells with broad distribution throughout the retina, confirming successful correction of the mutation. These data suggest that a simplified form of genome editing mediated by CRISPR, as described here, could be further developed to repair  RPGR  ORF15  mutations in vivo.

Restoration of RPGR expression in vivo using CRISPR/Cas9 gene editing