Downregulation of rhodopsin is an effective therapeutic strategy in ameliorating peripherin-2-associated inherited retinal disorders

AbstractGiven the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for PRPH2 pathogenic variants. To test the hypothesis that formation of the elongated discs in presence of PRPH2 pathogenic variants is due to the presence of the full complement of rhodopsin in absence of the required amounts of functional PRPH2. Here we demonstrate the therapeutic potential of reducing rhodopsin levels in ameliorating disease phenotype in knockin models for p.Lys154del (c.458-460del) and p.Tyr141Cys (c.422 A > G) in PRPH2. Reducing rhodopsin levels improves physiological function, mitigates the severity of disc abnormalities, and decreases retinal gliosis. Additionally, intravitreal injections of a rhodopsin-specific antisense oligonucleotide successfully enhance the physiological function of photoreceptors and improves the ultrastructure of discs in mutant mice. Presented findings shows that reducing rhodopsin levels is an effective therapeutic strategy for the treatment of inherited retinal degeneration associated with PRPH2 pathogenic variants.

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References

80

[1]

Nuzbrokh, Y., Ragi, S. D. & Tsang, S. H. Gene therapy for inherited retinal diseases. Ann. Transl. Med. 9, 1278 (2021). 10.21037/atm-20-4726

[2]

Inherited retinal diseases: Therapeutics, clinical trials and end points—A review

Michalis Georgiou, Kaoru Fujinami, Michel Michaelides

Clinical & Experimental Ophthalmology 2021 10.1111/ceo.13917

[3]

Sanjurjo-Soriano, C. & Kalatzis, V. Guiding lights in genome editing for inherited retinal disorders: implications for gene and cell therapy. Neural plasticity 2018, 5056279 (2018). 10.1155/2018/5056279

[4]

Nuzbrokh, Y., Kassotis, A. S., Ragi, S. D., Jauregui, R. & Tsang, S. H. Treatment-emergent adverse events in gene therapy trials for inherited retinal diseases: a narrative review. Ophthalmol. Ther. 9, 709–724 (2020). 10.1007/s40123-020-00287-1

[5]

Conley, S. M. et al. Delineating the clinical phenotype of patients with the c.629C>G, p.Pro210Arg mutation in peripherin-2. Investig. Ophthalmol. Vis. Sci. 63, 19 (2022). 10.1167/iovs.63.8.19

[6]

Coco-Martin R. M., Sanchez-Tocino H. T., Desco C., Usategui-Martin R., Telleria J. J. PRPH2-related retinal diseases: broadening the clinical spectrum and describing a new mutation. Genes 11, 773 (2020). 10.3390/genes11070773

[7]

Conley, S. M., Stuck, M. W., Watson, J. N. & Naash, M. I. Rom1 converts Y141C-Prph2-associated pattern dystrophy to retinitis pigmentosa. Hum. Mol. Genet. 26, 509–518 (2017).

[8]

Loewen, C. J., Moritz, O. L. & Molday, R. S. Molecular characterization of peripherin-2 and rom-1 mutants responsible for digenic retinitis pigmentosa. J. Biol. Chem. 276, 22388–22396 (2001). 10.1074/jbc.m011710200

[9]

Loewen, C. J., Moritz, O. L., Tam, B. M., Papermaster, D. S. & Molday, R. S. The role of subunit assembly in peripherin-2 targeting to rod photoreceptor disk membranes and retinitis pigmentosa. Mol. Biol. cell 14, 3400–3413 (2003). 10.1091/mbc.e03-02-0077

[10]

Nour, M., Ding, X. Q., Stricker, H., Fliesler, S. J. & Naash, M. I. Modulating expression of peripherin/rds in transgenic mice: critical levels and the effect of overexpression. Investig. Ophthalmol. Vis. Sci. 45, 2514–2521 (2004). 10.1167/iovs.04-0065

[11]

Hawkins, R. K., Jansen, H. G. & Sanyal, S. Development and degeneration of retina in rds mutant mice: photoreceptor abnormalities in the heterozygotes. Exp. eye Res. 41, 701–720 (1985). 10.1016/0014-4835(85)90179-4

[12]

Cheng, T. et al. The effect of peripherin/rds haploinsufficiency on rod and cone photoreceptors. J. Neurosci. Off. J. Soc. Neurosci. 17, 8118–8128 (1997). 10.1523/jneurosci.17-21-08118.1997

[13]

Chakraborty, D., Conley, S. M., Zulliger, R. & Naash, M. I. The K153Del PRPH2 mutation differentially impacts photoreceptor structure and function. Hum. Mol. Genet. 25, 3500–3514 (2016). 10.1093/hmg/ddw193

[14]

Stuck, M. W., Conley, S. M. & Naash, M. I. The Y141C knockin mutation in RDS leads to complex phenotypes in the mouse. Hum. Mol. Genet. 23, 6260–6274 (2014). 10.1093/hmg/ddu345

[15]

Ding, X. Q. et al. The R172W mutation in peripherin/rds causes a cone-rod dystrophy in transgenic mice. Hum. Mol. Genet. 13, 2075–2087 (2004). 10.1093/hmg/ddh211

[16]

Chakraborty, D. et al. Novel molecular mechanisms for Prph2-associated pattern dystrophy. FASEB J.: Off. Publ. Federation Am. Societies Exp. Biol. 34, 1211–1230 (2020). 10.1096/fj.201901888r

[17]

Stricker, H. M., Ding, X. Q., Quiambao, A., Fliesler, S. J. & Naash, M. I. The Cys214->Ser mutation in peripherin/rds causes a loss-of-function phenotype in transgenic mice. Biochem. J. 388, 605–613 (2005). 10.1042/bj20041960

[18]

Kedzierski, W. et al. Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa. Proc. Natl Acad. Sci. USA 98, 7718–7723 (2001). 10.1073/pnas.141124198

[19]

Weleber, R. G., Carr, R. E., Murphey, W. H., Sheffield, V. C. & Stone, E. M. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch. Ophthalmol. 111, 1531–1542 (1993). 10.1001/archopht.1993.01090110097033

[20]

Boon, C. J. et al. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br. J. Ophthalmol. 91, 1504–1511 (2007). 10.1136/bjo.2007.115659

[21]

Francis, P. J. et al. Genetic and phenotypic heterogeneity in pattern dystrophy. Br. J. Ophthalmol. 89, 1115–1119 (2005). 10.1136/bjo.2004.062695

[22]

Yang, Z. et al. A novel RDS/peripherin gene mutation associated with diverse macular phenotypes. Ophthalmic Genet. 25, 133–145 (2004). 10.1080/13816810490514388

[23]

Vaclavik, V., Tran, H. V., Gaillard, M. C., Schorderet, D. F. & Munier, F. L. Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections. Retina 32, 1942–1949 (2012). 10.1097/iae.0b013e31824b32e4

[24]

Dryja, T. P., Hahn, L. B., Kajiwara, K. & Berson, E. L. Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa. Investigative Ophthalmol. Vis. Sci. 38, 1972–1982 (1997).

[25]

Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018

Olivier J. Wouters, Martin McKee, Jeroen Luyten

JAMA 2020 10.1001/jama.2020.1166

[26]

Wen, X. H. et al. Overexpression of rhodopsin alters the structure and photoresponse of rod photoreceptors. Biophys. J. 96, 939–950 (2009). 10.1016/j.bpj.2008.10.016

[27]

Chakraborty, D., Conley, S. M., Al-Ubaidi, M. R. & Naash, M. I. Initiation of rod outer segment disc formation requires RDS. PloS one 9, e98939 (2014). 10.1371/journal.pone.0098939

[28]

Rakshit, T. & Park, P. S. Impact of reduced rhodopsin expression on the structure of rod outer segment disc membranes. Biochemistry 54, 2885–2894 (2015). 10.1021/acs.biochem.5b00003

[29]

Jastrzebska, B. et al. Rhodopsin-transducin heteropentamer: three-dimensional structure and biochemical characterization. J. Struct. Biol. 176, 387–394 (2011). 10.1016/j.jsb.2011.08.016

[30]

Toda, K., Bush, R. A., Humphries, P. & Sieving, P. A. The electroretinogram of the rhodopsin knockout mouse. Vis. Neurosci. 16, 391–398 (1999). 10.1017/s0952523899162187

[31]

Sung, C. H., Makino, C., Baylor, D. & Nathans, J. A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment. J. Neurosci. Off. J. Soc. Neurosci. 14, 5818–5833 (1994). 10.1523/jneurosci.14-10-05818.1994

[32]

Tan, E. et al. The relationship between opsin overexpression and photoreceptor degeneration. Investigative Ophthalmol. Vis. Sci. 42, 589–600 (2001).

[33]

Hollingsworth, T. J. & Gross, A. K. Defective trafficking of rhodopsin and its role in retinal degenerations. Int. Rev. cell Mol. Biol. 293, 1–44 (2012). 10.1016/b978-0-12-394304-0.00006-3

[34]

Lem, J. et al. Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc. Natl Acad. Sci. USA 96, 736–741 (1999). 10.1073/pnas.96.2.736

[35]

Makino, C. L. et al. Rhodopsin expression level affects rod outer segment morphology and photoresponse kinetics. PloS one 7, e37832 (2012). 10.1371/journal.pone.0037832

[36]

Humphries, M. M. et al. Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nat. Genet. 15, 216–219 (1997). 10.1038/ng0297-216

[37]

Lewis, T. R. et al. Photoreceptor Disc Enclosure Is Tightly Controlled by Peripherin-2 Oligomerization. J. Neurosci. Off. J. Soc. Neurosci. 41, 3588–3596 (2021). 10.1523/jneurosci.0041-21.2021

[38]

Murray, S. F. et al. Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration. Inv. Ophthalmol. Vis. Sci. 56, 6362–6375 (2015). 10.1167/iovs.15-16400

[39]

Keen, T. J. & Inglehearn, C. F. Mutations and polymorphisms in the human peripherin-RDS gene and their involvement in inherited retinal degeneration. Hum. Mutat. 8, 297–303 (1996). 10.1002/(sici)1098-1004(1996)8:4<297::aid-humu1>3.0.co;2-5

[40]

Ding, J. D., Salinas, R. Y. & Arshavsky, V. Y. Discs of mammalian rod photoreceptors form through the membrane evagination mechanism. J. Cell Biol. 211, 495–502 (2015). 10.1083/jcb.201508093

[41]

Conley, S. M. et al. Prph2 initiates outer segment morphogenesis but maturation requires Prph2/Rom1 oligomerization. Hum. Mol. Genet. 28, 459–475 (2019).

[42]

Bringmann, A. & Reichenbach, A. Role of Muller cells in retinal degenerations. Front. Biosci. J. virtual Libr. 6, E72–E92 (2001). 10.2741/bringman

[43]

Müller cells in the healthy and diseased retina

A BRINGMANN, T PANNICKE, J GROSCHE et al.

Progress in Retinal and Eye Research 2006 10.1016/j.preteyeres.2006.05.003

[44]

de Hoz, R. et al. Retinal macroglial responses in health and disease. BioMed. Res. Int. 2016, 2954721 (2016). 10.1155/2016/2954721

[45]

Fernandez-Sanchez, L., Lax, P., Campello, L., Pinilla, I. & Cuenca, N. Astrocytes and muller cell alterations during retinal degeneration in a transgenic rat model of retinitis pigmentosa. Front. Cell. Neurosci. 9, 484 (2015). 10.3389/fncel.2015.00484

[46]

Wensel, T. G. et al. Structural and molecular bases of rod photoreceptor morphogenesis and disease. Prog. Retinal Eye Res. 55, 32–51 (2016). 10.1016/j.preteyeres.2016.06.002

[47]

Kocaoglu, O. P. et al. Photoreceptor disc shedding in the living human eye. Biomed. Opt. Express 7, 4554–4568 (2016). 10.1364/boe.7.004554

[48]

Spencer, W. J., Lewis, T. R., Pearring, J. N. & Arshavsky, V. Y. Photoreceptor discs: built like ectosomes. Trends Cell Biol. 30, 904–915 (2020). 10.1016/j.tcb.2020.08.005

[49]

Kedzierski, W., Lloyd, M., Birch, D. G., Bok, D. & Travis, G. H. Generation and analysis of transgenic mice expressing P216L-substituted rds/peripherin in rod photoreceptors. Investigative Ophthalmol. Vis. Sci. 38, 498–509 (1997).

[50]

McNally, N. et al. Murine model of autosomal dominant retinitis pigmentosa generated by targeted deletion at codon 307 of the rds-peripherin gene. Hum. Mol. Genet. 11, 1005–1016 (2002). 10.1093/hmg/11.9.1005

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Published: Jun 04, 2024
Vol/Issue: 15(1)
License: View

Authors

C

Christian T. Rutan Woods

M

Mustafa S. Makia

Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA

Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA; College of Optometry, University of Houston, Houston, TX 77204, USA; Department of Biology and Biochemistry, University of Houston, TX 77204, USA

M

Muayyad R. Al-Ubaidi

Funding

U.S. Department of Health & Human Services | NIH | National Eye Institute Award: EY010609

Cite This Article

Christian T. Rutan Woods, Mustafa S. Makia, Tylor R. Lewis, et al. (2024). Downregulation of rhodopsin is an effective therapeutic strategy in ameliorating peripherin-2-associated inherited retinal disorders. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-48846-5

Downregulation of rhodopsin is an effective therapeutic strategy in ameliorating peripherin-2-associated inherited retinal disorders

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