RPGR-Associated Retinal Degeneration in Human X-Linked RP and a Murine Model

Abstract

RPGR mutations lead to progressive loss of rod and cone vision, but show different patterns of residual photoreceptor disease expression. Knowledge of the patterns should guide treatment strategies. Rpgr-cko mice had onset of degeneration at relatively young ages and progressive photoreceptor disease. The natural history in this model will permit preclinical proof-of-concept studies to be designed and such studies should advance progress toward human therapy.

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

“…RPGR overexpression in the wild-type retina will also inform as to whether similar gene therapy intervention could be safely considered for some carrier female patients. Finally, pursuing detailed phenotypic characterization of XLRP patients (Jacobson et al 1997;Lorenz et al 2003;Aleman et al 2007;Huang et al 2012) is necessary to establish valid outcome measures of therapeutic efficacy for future human clinical trials. A patent application on AAV-mediated gene therapy for RPGR X-linked retinal degeneration has been filed (PCT/US2013/022628).…”

“…Depending on the degree of abnormality in retina-wide measurements of cone versus rod function, clinical diagnoses have included Xlinked cone-rod dystrophy, cone dystrophy, or macular degeneration (Mears et al 2000;Ayyagari et al 2002;Demirci et al 2002;Yang et al 2002;Ebenezer et al 2005;Pelletier et al 2007;Thiadens et al 2011;Beltran et al 2012). Retinally colocalized measures of function have often shown both rod and cone loss (Jacobson et al 1997;Lorenz et al 2003;Huang et al 2012) consistent with expression of the RPGR gene product in rod and cone cilia (Hong et al 2000(Hong et al , 2003Roepman et al 2000;Khanna et al 2005;Shu et al 2005). High allelic heterogeneity has been implied as cause for the spectrum of severity and phenotypes encountered between families carrying different RPGR mutations, and there is evidence that genetic modifiers may contribute to intra-familial phenotypic divergence (Keith et al 1991;Walia et al 2008;Ruddle et al 2009;Fahim et al 2011).…”

“…The description of the phenotypes of several mouse models of RPGR disease, including XLRP (Hong et al 2000(Hong et al , 2004Brunner et al 2010;Wright et al 2011;Huang et al 2012;Thompson et al 2012) and cone-rod dystrophy (Brunner et al 2010), have been published. Evidence that mice sharing the same RPGR mutation but on a different genetic background can express a different disease phenotype further highlights the potential role of genetic modifiers (Brunner et al 2010).…”

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

“…The natural course of RPGR-XLRP disease is severe, with males showing loss of night vision in the first decade of life (23). The disease onset in the naturally occurring or Rpgr KO mouse models is very late (23)(24)(25) as it corresponds to 35 human years (26), whereas the disease onset in two naturally occurring canine models of RPGR-XLRP (27)(28)(29) are earlier and correspond better to the human disease time course. Gene augmentation delivered by means of an adeno-associated viral (AAV) vector has been shown to be efficient in both the dog and mouse models (30,31).…”

“…There are currently more than 300 distinct mutations (rpgr.hgu.mrc.ac.uk/supplementary/) identified in RPGR, and the majority are found in a glutamic acidrich domain within exon ORF15 (21,22). The natural course of RPGR-XLRP disease is severe, with males showing loss of night vision in the first decade of life (23). The disease onset in the naturally occurring or Rpgr KO mouse models is very late (23)(24)(25) as it corresponds to 35 human years (26), whereas the disease onset in two naturally occurring canine models of RPGR-XLRP (27)(28)(29) are earlier and correspond better to the human disease time course.…”