RPGR and X-linked Retinitis Pigmentosa

Summary

Inherited retinal degenerations (IRDs), including retinitis pigmentosa (RP) refer to a heterogeneous group of Mendelian disorders caused by mutations in over 200 genes and resulting in vision loss due to loss of structure and function of rod and/or cone photoreceptors. Among the most common genetic causes of IRDs are mutations in the RPGR gene located on the X-chromosome; by far the majority of the RPGR mutations are located in the ORF15 exon of the gene. Most, but not all, patients with RPGR-ORF15 mutations are diagnosed with X-linked RP (XLRP). In addition to causing visual disability in humans, naturally-occurring mutations in ORF15 exon are also found in dogs and mice with retinal degeneration. The exact function of RPGR in the rod and cone photoreceptors remains poorly understood but it is suggested to be involved in regulating ciliary transport. Successful experiments in gene augmentation therapy at different disease stages of dogs with RPGR-ORF15 mutations have set a clear path for clinical trials of gene augmentation therapy in patients.

Cideciyan Lab has been involved with better understanding and potentially treating XLRP for over 25 years. Our work includes details of disease expression in hemizygous male patients and heterozygous female carriers (see refs below: 2,3,7,9,21,24,85,90,127,166), as well as understanding of retinal disease features in mice (127,168) and dogs (126,137,142,154,176). More recently, the lab has been concentrating on gene augmentation therapy applied to dogs with RPGR-ORF15 mutations (126,142,154,176,206,210), specific disease features in patients in order to determine when and where to treat, and what outcomes to use (168,194), and hypotheses based on RPGR isoform imbalance in different ORF15 mutations (215).

20 Publications on XLRP and RPGR

215. Moreno-Leon L, West EL, O'Hara-Wright M, Li L, Nair R, He J, Anand M, Sahu B, Chavali VRM, Smith AJ, Ali RR, Jacobson SG, CIDECIYAN AV, Khanna H. RPGR isoform imbalance causes ciliary defects due to exon ORF15 mutations in X-linked retinitis pigmentosa (XLRP). Human Molecular Genetics, 29:3706-3716, 2020. [PubMed] [DOI]

210. Song C, Dufour VLL, CIDECIYAN AV, Ye GJ, Swider M, Newmark J, Timmers A, Robinson P, Knop DR, Chulay JD, Jacobson SG, Aguirre GD, Beltran WA, Shearman MS. Dose range finding studies with two RPGR transgenes in a canine model of X-linked retinitis pigmentosa treated with subretinal gene therapy. Human Gene Therapy, 31:743-755, 2020. [PubMed]

206. Dufour VLL, CIDECIYAN AV, Ye GJ, Song C, Timmers A, Habecker P, Pan W, Weinstein N, Swider M, Durham A, Ying GS, Robinson P, Jacobson SG, Knop DR, Chulay JD, Shearman MS, Aguirre GD, Beltran WA. Toxicity and efficacy evaluation of an AAV vector expressing codon-optimized RPGR delivered by subretinal injection in a canine model of X-linked retinitis pigmentosa. Human Gene Therapy, 31:253-267, 2020. [PubMed]

194. CIDECIYAN AV, Charng J, Roman AJ, Sheplock R, Garafalo AV, Heon E, Jacobson SG. Progression in X-linked retinitis pigmentosa due to ORF15-RPGR mutations: Assessment of localized vision changes over 2 years. Investigative Ophthalmology & Visual Science 59:4558-4566, 2018. [PubMed]

176. Beltran WA, CIDECIYAN AV, Boye SE, Ye G-J, Iwabe S, Dufour VL, Marinho LF, Swider M, Kosyk MS, Sha J, Boye SL, Peterson JJ, Witherspoon CD, Alexander JJ, Ying G-S, Shearman MS, Chulay JD, Hauswirth WW, Gamlin PD, Jacobson SG, Aguirre GD. Optimization of retinal gene therapy for X-linked retinitis pigmentosa due to RPGR mutations. Molecular Therapy, 25:1866-1880, 2017. [PubMed]

168. Charng J, CIDECIYAN AV, Jacobson SG, Sumaroka A, Schwartz SB, Swider M, Roman AJ, Sheplock R, Anand M, Peden MC, Khanna H, Heon E, Wright AF, Swaroop A. Variegated yet non-random rod and cone photoreceptor disease patterns in RPGR-ORF15-associated retinal degeneration. Human Molecular Genetics 25:5444–5459, 2016. [PubMed]

166. Downs LM, Scott EM, CIDECIYAN AV, Iwabe S, Dufour V, Gardiner KL, Genini S, Marinho LF, Sumaroka A, Kosyk MS, Swider M, Aguirre GK, Jacobson SG, Beltran WA, Aguirre GD. Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation.  Human Molecular Genetics 25:4211-4226, 2016. [PubMed]

154. Beltran WA, CIDECIYAN AV, Iwabea S, Swider M, Kosyk MS, McDaida K, Martynyuka I, Ying G-S, Shaffer J, Deng W-T, Boye SL, Lewin AS, Hauswirth WW, Jacobson SG, Aguirre GD. Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease. Proceedings of the National Academy of Sciences USA 112:E5844-53, 2015. [PubMed] [NEI Press Release] [Penn Press Release] [PDF]

142. Beltran WA, CIDECIYAN AV, Lewin AS, Hauswirth WW, Jacobson SG, Aguirre GD. Gene augmentation for X-linked retinitis pigmentosa caused by mutations in RPGR. Cold Spring Harbor Perspectives in Medicine 5:a017392, 2015. [PubMed]

137. Beltran WA, CIDECIYAN AV, Guziewicz KE, Iwabe S, Swider M, Scott EM, Savina SV, Ruthel G, Stefano F, Zhang L, Zorger R, Sumaroka A, Jacobson SG, Aguirre GD. Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations. PLoS One 9:e90390, 2014. [PubMed] [Penn News] [PDF]

127. Huang WC, Wright AF, Roman AJ, CIDECIYAN AV, Manson FD, Gewaily DY, Schwartz SB, Sadigh S, Limberis MP, Bell P, Wilson JM, Swaroop A, Jacobson SG. RPGR-associated retinal degeneration in human X-linked RP and a murine model. Investigative Ophthalmology & Visual Science 53:5594–5608, 2012. [PubMed]

126. Beltran WA, CIDECIYAN AV, Lewin AS, Iwabe1 S, Khanna H, Sumaroka A, Chiodo VA, Fajardo DS, Román AJ, Deng W-T, Swider M, Alemán TS, Boye SL, Genini S,Swaroop A, Hauswirth WW, Jacobson SG, Aguirre GD. Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proceedings of the National Academy of Sciences USA 109:2132-2137, 2012. [PubMed] [Penn News] [PDF]

90. Aleman TS, CIDECIYAN AV, Sumaroka A, Schwartz SB, Roman AJ, Windsor EAM, Steinberg JD, Branham K, Othman M, Swaroop A, Jacobson SG. Inner retinal abnormalities in X-linked retinitis pigmentosa with RPGR mutations. Investigative Ophthalmology & Visual Science, 48:4759-4765, 2007. [PubMed]

85. CIDECIYAN AV, Aleman TS, Jacobson SG, Khanna H, Sumaroka A, Aguirre GK, Schwartz SB, Windsor EAM, He S, Chang B, Stone EM, Swaroop A. Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Human Mutation, 28:1074-1083, 2007. [PubMed]

24. Gieser L, Fujita R, Goring HHH, Ott J, Hoffman DR, CIDECIYAN AV, Birch DG, Jacobson SG, Swaroop A. A novel locus (RP24) for X-linked retinitis pigmentosa maps to Xq26-27. Americal Journal of Human Genetics, 63:1439-1447, 1998. [PubMed]

21. Jacobson SG, Buraczynska M, Milam AH, Chen C, Jarvalainen M, Fujita R, Wu W, Huang Y, CIDECIYAN AV, Swaroop A. Disease expression in X-linked retinitis pigmentosa caused by a putative null mutation in the RPGR gene. Investigative Ophthalmology & Visual Science, 38:1983-1997, 1997. [PubMed]

9. CIDECIYAN AV. Registration of ocular fundus images by cross-correlation of triple invariant image descriptors. IEEE Engineering in Medicine & Biology 14:52-58, 1995.

7. CIDECIYAN AV and Jacobson SG. Image analysis of the tapetal-like reflex in heterozygotes of X-linked retinitis pigmentosa. Investigative Ophthalmology & Visual Science, 35:3812-3824, 1994. [PubMed]

3. Nagel JH and CIDECIYAN AV. Digital analysis of high resolution fundus images. Biomedical Engineering: Application, Basis and Communication 4:645-682, 1992.

2. Jacobson SG, Roman AJ, CIDECIYAN AV, Robey MG, Iwata T and Inana G. X-linked retinitis pigmentosa: functional phenotype of an RP2 genotype. Investigative Ophthalmology & Visual Science, 33:3481-3492, 1992. [PubMed]

Last updated January 24, 2021