Photoreceptor rescue by an abbreviated human RPGR gene in a murine model of X-linked retinitis pigmentosa

Gene Therapy
B PawlykT Li

Abstract

The X-linked RP3 gene codes for the ciliary protein RPGR and accounts for over 10% of inherited retinal degenerations. The critical RPGR-ORF15 splice variant contains a highly repetitive purine-rich linker region that renders it unstable and difficult to adapt for gene therapy. To test the hypothesis that the precise length of the linker region is not critical for function, we evaluated whether adeno-associated virus-mediated replacement gene therapy with a human ORF15 variant containing in-frame shortening of the linker region could reconstitute RPGR function in vivo. We delivered human RPGR-ORF15 replacement genes with deletion of most (314 codons, 'short form') or 1/3 (126 codons, 'long form') of the linker region to Rpgr null mice. Human RPGR-ORF15 expression was detected post treatment with both forms of ORF15 transgenes. However, only the long form correctly localized to the connecting cilia and led to significant functional and morphological rescue of rods and cones. Thus the highly repetitive region of RPGR is functionally important but that moderate shortening of its length, which confers the advantage of added stability, preserves its function. These findings provide a theoretical basis for optimizing replacement gene...Continue Reading

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Citations

May 11, 2016·Proceedings of the National Academy of Sciences of the United States of America·Xun SunTiansen Li
Oct 25, 2016·The Journal of Molecular Diagnostics : JMD·Jianli LiLee-Jun C Wong
Mar 6, 2018·British Medical Bulletin·Neruban KumaranJames W B Bainbridge
Aug 23, 2017·Journal of Neural Engineering·Priya R Gupta, Rachel M Huckfeldt
Oct 24, 2017·Expert Opinion on Biological Therapy·Nicholas A MoorePeter Bracha
Jul 19, 2018·Ophthalmic Surgery, Lasers & Imaging Retina·Benjamin BakallKendra A Klein
Oct 4, 2018·Human Gene Therapy. Clinical Development·Chunjuan SongGuo-Jie Ye
Mar 29, 2019·International Journal of Molecular Sciences·Kentaro KurataYoshihiro Hotta
Aug 3, 2019·Molecular Genetics & Genomic Medicine·Yu ZhangXiaoyan Ding
Sep 7, 2019·Genes·Jasmina Cehajic KapetanovicRobert E MacLaren
Sep 13, 2018·Investigative Ophthalmology & Visual Science·Artur V CideciyanSamuel G Jacobson
Mar 20, 2020·Physiological Reviews·Sonja KleinlogelTobias Moser
Jan 10, 2019·Proceedings of the National Academy of Sciences of the United States of America·Qihong ZhangVal C Sheffield
Oct 16, 2019·Expert Opinion on Biological Therapy·Cristina Martinez-Fernandez De La CamaraRobert E MacLaren
Jul 31, 2018·Expert Opinion on Orphan Drugs·Cristina Martinez-Fernandez De La CamaraRobert E MacLaren
Mar 10, 2021·Clinical & Experimental Ophthalmology·Michalis GeorgiouMichel Michaelides
Aug 30, 2020·Progress in Retinal and Eye Research·Samantha R De SilvaOmar A Mahroo
Jul 15, 2021·Gene Therapy·Jessica D GumersonTiansen Li
Sep 30, 2021·International Ophthalmology Clinics·Aumer ShughouryEmmett T Cunningham
Sep 30, 2021·International Ophthalmology Clinics·Michalis GeorgiouMichel Michaelides

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Methods Mentioned

BETA
GTPase
transgenic
PCR
transfection
dot blot
light microscopy

Software Mentioned

Labview
SAS
JMP Pro

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