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Development of therapeutic splice-switching oligonucleotides.

Disterer, P; Kryczka, A; Liu, Y; Badi, YE; Wong, JJ; Owen, JS; Khoo, B; (2014) Development of therapeutic splice-switching oligonucleotides. Hum Gene Ther , 25 (7) pp. 587-598. 10.1089/hum.2013.234. Green open access

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Abstract

Synthetic splice-switching oligonucleotides (SSOs) target nuclear pre-mRNA molecules to change exon splicing and generate an alternative protein isoform. Clinical trials with two competitive SSO drugs are underway to treat Duchenne Muscular Dystrophy (DMD). Beyond DMD, many additional therapeutic applications are possible, with some in phase I clinical trials or advanced preclinical evaluation. Here, we present an overview of the central factors involved in developing therapeutic SSOs for the treatment of diseases. The selection of susceptible pre-mRNA target sequences, as well as the design and chemical modification of SSOs to increase SSO stability and effectiveness, are key initial considerations. Identification of effective SSO target sequences is still largely empirical and published guidelines are not a universal guarantee for success. Specifically, exonic-targeted SSOs, which are successful in modifying dystrophin splicing, can be ineffective for splice-switching in other contexts. Chemical modifications, importantly, are associated with certain characteristic toxicities, which need to be addressed as target diseases require chronic treatment with SSOs. Moreover, SSO delivery in adequate quantities to the nucleus of target cells without toxicity can prove difficult. Lastly, the means by which these SSOs are administered needs to be acceptable to the patient. Engineering an efficient therapeutic SSO, therefore, necessarily entails a compromise between desirable qualities and effectiveness. Here, we describe how the application of optimal solutions may differ from case to case.

Type: Article
Title: Development of therapeutic splice-switching oligonucleotides.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/hum.2013.234
Publisher version: http://dx.doi.org/10.1089/hum.2013.234
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 3.0 United States License. You are free to copy, distribute, transmit and adapt this work, but you must attribute this work as ‘‘Human Gene Therapy. Copyright 2014 Mary Ann Liebert, Inc. http://liebertpub.com/hum, used under a Creative Commons Attribution License: http://creativecommons.org/licenses/by/3.0/us/"
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
URI: https://discovery.ucl.ac.uk/id/eprint/1430068
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