Skip to main content Accessibility help

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations



The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30–50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.


Corresponding author

Address correspondence to: Kerstin Nagel-Wolfrum, Department of Cell and Matrix Biology, Johannes Gutenberg-University, Institute of Zoology, D-55099 Mainz, Germany. E-mail:


Hide All
Amrani, N., Ganesan, R., Kervestin, S., Mangus, D.A., Ghosh, S. & Jacobson, A. (2004). A faux 3′-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 432, 112118.
Athanasiou, D., Aguila, M., Bevilacqua, D., Novoselov, S.S., Parfitt, D.A. & Cheetham, M.E. (2013). The cell stress machinery and retinal degeneration. FEBS Letters 587, 20082017.
Bidou, L., Allamand, V., Rousset, J.P. & Namy, O. (2012). Sense from nonsense: Therapies for premature stop codon diseases. Trends in Molecular Medicine 18, 679688.
Boye, S.E., Boye, S.L., Lewin, A.S. & Hauswirth, W.W. (2013). A comprehensive review of retinal gene therapy. Molecular Therapy 21, 509519.
Burke, J.F. & Mogg, A.E. (1985). Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin. Nucleic Acids Research 13, 62656272.
Chernikov, V.G., Terekhov, S.M., Krokhina, T.B., Shishkin, S.S., Smirnova, T.D., Kalashnikova, E.A., Adnoral, N.V., Rebrov, L.B., Denisov-Nikol’skii, Y.I. & Bykov, V.A. (2003). Comparison of cytotoxicity of aminoglycoside antibiotics using a panel cellular biotest system. Bulletin of Experimental Biology Medicine 135, 103105.
Cideciyan, A.V., Jacobson, S.G., Beltran, W.A., Sumaroka, A., Swider, M., Iwabe, S., Roman, A.J., Olivares, M.B., Schwartz, S.B., Komaromy, A.M., Hauswirth, W.W. & Aguirre, G.D. (2013). Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proceedings of the National Academy Sciences of the United States of America 110, E517E525.
Cohen, M., Bitner-Glindzicz, M. & Luxon, L. (2007). The changing face of Usher syndrome: Clinical implications. International Journal of Audiology 46, 8293.
Du, M., Keeling, K.M., Fan, L., Liu, X. & Bedwell, D.M. (2009). Poly-L-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model. Journal of Biological Chemistry 284, 68856892.
Estrada-Cuzcano, A., Roepman, R., Cremers, F.P., den Hollander, A.I. & Mans, D.A. (2012). Non-syndromic retinal ciliopathies: Translating gene discovery into therapy. Human Molecular Genetics 21, R111R124.
Finkel, R.S. (2010). Read-through strategies for suppression of nonsense mutations in Duchenne/Becker muscular dystrophy: Aminoglycosides and ataluren (PTC124). Journal of Child Neurology 25, 11581164.
Floquet, C., Rousset, J.P. & Bidou, L. (2011). Readthrough of premature termination codons in the adenomatous polyposis coli gene restores its biological activity in human cancer cells. PLoS One 6, e24125.
Gatti, R.A. (2012). SMRT compounds correct nonsense mutations in primary immunodeficiency and other genetic models. Annals of the New York Academy of Sciences 1250, 3340.
Goldmann, T., Overlack, N., Moller, F., Belakhov, V., van Wyk, M., Baasov, T., Wolfrum, U. & Nagel-Wolfrum, K. (2012). A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Molecular Medicine 4, 11861199.
Goldmann, T., Overlack, N., Wolfrum, U. & Nagel-Wolfrum, K. (2011). PTC124-mediated translational readthrough of a nonsense mutation causing Usher syndrome type 1C. Human Gene Therapy 22, 537547.
Goldmann, T., Rebibo-Sabbah, A., Overlack, N., Nudelman, I., Belakhov, V., Baasov, T., Ben Yosef, T., Wolfrum, U. & Nagel-Wolfrum, K. (2010). Beneficial read-through of a USH1C nonsense mutation by designed aminoglycoside NB30 in the retina. Investigative Ophthalmology Visual Science 51, 66716680.
Gregory-Evans, K., Po, K., Chang, F. & Gregory-Evans, C.Y. (2012). Pharmacological enhancement of ex vivo gene therapy neuroprotection in a rodent model of retinal degeneration. Ophthalmic Research 47, 3238.
Gregory-Evans, C.Y., Wang, X., Wasan, K.M., Zhao, J., Metcalfe, A.L. & Gregory-Evans, K. (2014). Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects. Journal of Clinical Investigation 124, 111116.
Guerin, K., Gregory-Evans, C.Y., Hodges, M.D., Moosajee, M., Mackay, D.S., Gregory-Evans, K. & Flannery, J.G. (2008). Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa. Experimental Eye Research 87, 197207.
Hainrichson, M., Nudelman, I. & Baasov, T. (2008). Designer aminoglycosides: The race to develop improved antibiotics and compounds for the treatment of human genetic diseases. Organic & Biomolecular Chemistry 6, 227239.
Hirawat, S., Welch, E.M., Elfring, G.L., Northcutt, V.J., Paushkin, S., Hwang, S., Leonard, E.M., Almstead, N.G., Ju, W., Peltz, S.W. & Miller, L.L. (2007). Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. Journal of Clinical Pharmacology 47, 430444.
Jackson, R.J., Hellen, C.U. & Pestova, T.V. (2012). Termination and post-termination events in eukaryotic translation. Advances in Protein Chemistry and Structural Biology 86, 4593.
Jung, M.E., Ku, J.M., Du, L., Hu, H. & Gatti, R.A. (2011). Synthesis and evaluation of compounds that induce readthrough of premature termination codons. Bioorganic & Medicinal Chemistry Letters 21, 58425848.
Kandasamy, J., Atia-Glikin, D., Belakhov, V. & Baasov, T. (2011). Repairing faulty genes by aminoglycosides: Identification of new pharmacophore with enhanced suppression of disease-causing nonsense mutations. MedChemComm 2, 165171.
Kayali, R., Ku, J.M., Khitrov, G., Jung, M.E., Prikhodko, O. & Bertoni, C. (2012). Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Human Molecular Genetics 21, 40074020.
Keeling, K.M. & Bedwell, D.M. (2002). Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system. Journal of Molecular Medicine 80, 367376.
Keeling, K.M. & Bedwell, D.M. (2011). Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases. Wiley Interdisciplinary Reviews: RNA 2, 837852.
Keeling, K.M., Brooks, D.A., Hopwood, J.J., Li, P., Thompson, J.N. & Bedwell, D.M. (2001). Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Human Molecular Genetics 10, 291299.
Keeling, K.M., Wang, D., Conard, S.E. & Bedwell, D.M. (2012). Suppression of premature termination codons as a therapeutic approach. Critical Reviews in Biochemistry and Molecular Biology 47, 444463.
Keeling, K.M., Wang, D., Dai, Y., Murugesan, S., Chenna, B., Clark, J., Belakhov, V., Kandasamy, J., Velu, S.E., Baasov, T. & Bedwell, D.M. (2013). Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression. PLoS One 8, e60478.
Lee, H.L. & Dougherty, J.P. (2012). Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacology & Therapeutics 136, 227266.
Liang, H., Cavalcanti, A.R. & Landweber, L.F. (2005). Conservation of tandem stop codons in yeasts. Genome Biology 6, R31.
Linde, L. & Kerem, B. (2008). Introducing sense into nonsense in treatments of human genetic diseases. Trends in Genetics 24, 552563.
Lopez-Novoa, J.M., Quiros, Y., Vicente, L., Morales, A.I. & Lopez-Hernandez, F.J. (2011). New insights into the mechanism of aminoglycoside nephrotoxicity: An integrative point of view. Kidney International 79, 3345.
Manuvakhova, M., Keeling, K. & Bedwell, D.M. (2000). Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA 6, 10441055.
Moosajee, M., Gregory-Evans, K., Ellis, C.D., Seabra, M.C. & Gregory-Evans, C.Y. (2008). Translational bypass of nonsense mutations in zebrafish rep1, pax2.1 and lamb1 highlights a viable therapeutic option for untreatable genetic eye disease. Human Molecular Genetics 17, 39874000.
Nudelman, I., Glikin, D., Smolkin, B., Hainrichson, M., Belakhov, V. & Baasov, T. (2010). Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations. Bioorganic & Medicinal Chemistry 18, 37353746.
Nudelman, I., Rebibo-Sabbah, A., Cherniavsky, M., Belakhov, V., Hainrichson, M., Chen, F., Schacht, J., Pilch, D.S., Ben-Yosef, T. & Baasov, T. (2009). Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations. Journal of Medicinal Chemistry 52, 28362845.
Nudelman, I., Rebibo-Sabbah, A., Shallom-Shezifi, D., Hainrichson, M., Stahl, I., Ben Yosef, T. & Baasov, T. (2006). Redesign of aminoglycosides for treatment of human genetic diseases caused by premature stop mutations. Bioorganic & Medicinal Chemistry Letters 16, 63106315.
Overlack, N., Goldmann, T., Wolfrum, U. & Nagel-Wolfrum, K. (2011). Current therapeutic strategies for human Usher syndrome. In Usher Syndrome: Pathogenesis, Diagnosis and Therapy, ed. Ahuja, S., pp. 377395. Hauppauge, New York: Nova Science Publishers, Inc.
Peltz, S.W., Morsy, M., Welch, E.M. & Jacobson, A. (2013). Ataluren as an agent for therapeutic nonsense suppression. Annual Review of Medicine 64, 407425.
Perez, B., Rodriguez-Pombo, P., Ugarte, M. & Desviat, L.R. (2012). Readthrough strategies for therapeutic suppression of nonsense mutations in inherited metabolic disease. Molecular Syndromology 3, 230236.
Rebibo-Sabbah, A., Nudelman, I., Ahmed, Z.M., Baasov, T. & Ben Yosef, T. (2007). In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome. Human Genetics 122, 373381.
Wang, L., Zou, J., Shen, Z., Song, E. & Yang, J. (2012). Whirlin interacts with espin and modulates its actin-regulatory function: An insight into the mechanism of Usher syndrome type II. Human Molecular Genetics 21, 692710.
Warchol, M.E. (2010). Cellular mechanisms of aminoglycoside ototoxicity. Current Opinion in Otolaryngology & Head and Neck Surgery 18, 454458.
Welch, E.M., Barton, E.R., Zhuo, J., Tomizawa, Y., Friesen, W.J., Trifillis, P., Paushkin, S., Patel, M., Trotta, C.R., Hwang, S., Wilde, R.G., Karp, G., Takasugi, J., Chen, G., Jones, S., Ren, H., Moon, Y.C., Corson, D., Turpoff, A.A., Campbell, J.A., Conn, M.M., Khan, A., Almstead, N.G., Hedrick, J., Mollin, A., Risher, N., Weetall, M., Yeh, S., Branstrom, A.A., Colacino, J.M., Babiak, J., Ju, W.D., Hirawat, S., Northcutt, V.J., Miller, L.L., Spatrick, P., He, F., Kawana, M., Feng, H., Jacobson, A., Peltz, S.W. & Sweeney, H.L. (2007). PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 8791.
Wilschanski, M., Yahav, Y., Yaacov, Y., Blau, H., Bentur, L., Rivlin, J., Aviram, M., Bdolah-Abram, T., Bebok, Z., Shushi, L., Kerem, B. & Kerem, E. (2003). Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. The New England Journal of Medicine 349, 14331441.
Wolfrum, U. (2011). Protein Networks Related to the Usher Syndrome Gain Insights in the Molecular Basis of the Disease. In Usher Syndrome: Pathogenesis, Diagnosis and Therapy, ed. Satpal, A., pp. 5173. Hauppauge, New York: Nova Science Publishers.
Yang, J. (2012). Usher Syndrome: Genes, proteins, models, molecular mechanisms, and therapies. Hearing Loss, ed. Sadaf, N., pp. 293328. Rijeka, Croatia: InTech.
Zingman, L.V., Park, S., Olson, T.M., Alekseev, A.E. & Terzic, A. (2007). Aminoglycoside-induced translational read-through in disease: Overcoming nonsense mutations by pharmacogenetic therapy. Clinical Pharmacology and Therapeutics 81, 99103.


Related content

Powered by UNSILO

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.