Delivery is key: lessons learnt from developing splice-switching antisense therapies

Caroline Godfrey; Lourdes R. Desviat; Bård Smedsrød; France Piétri-Rouxel; Michela A. Denti; Petra Disterer; Stéphanie Lorain; Gisela Nogales-Gadea; Valentina Sardone; Rayan Anwar; Samir El Andaloussi; Taavi Lehto; Bernard Khoo; Camilla Brolin; Willeke M.C. van Roon-Mom; Aurélie Goyenvalle; Annemieke Aartsma-Rus; Virginia Arechavala-Gomeza

doi:10.15252/emmm.201607199

Delivery is key: lessons learnt from developing splice-switching antisense therapies

Caroline Godfrey, Lourdes R. Desviat, Bård Smedsrød, France Piétri-Rouxel, Michela A. Denti, Petra Disterer, Stéphanie Lorain, Gisela Nogales-Gadea, Valentina Sardone, Rayan Anwar, Samir El Andaloussi, Taavi Lehto, Bernard Khoo, Camilla Brolin, Willeke M.C. van Roon-Mom, Aurélie Goyenvalle, Annemieke Aartsma-Rus, Virginia Arechavala-Gomeza^*

^*Corresponding author for this work

Transcription, RNA, and Gene Medicine Program

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Abstract

The use of splice-switching antisense therapy is highly promising, with a wealth of pre-clinical data and numerous clinical trials ongoing. Nevertheless, its potential to treat a variety of disorders has yet to be realized. The main obstacle impeding the clinical translation of this approach is the relatively poor delivery of antisense oligonucleotides to target tissues after systemic delivery. We are a group of researchers closely involved in the development of these therapies and would like to communicate our discussions concerning the validity of standard methodologies currently used in their pre-clinical development, the gaps in current knowledge and the pertinent challenges facing the field. We therefore make recommendations in order to focus future research efforts and facilitate a wider application of therapeutic antisense oligonucleotides.

Original language	English
Journal	EMBO Molecular Medicine
Volume	9
Issue number	5
Pages (from-to)	545-557
Number of pages	13
ISSN	1757-4676
DOIs	https://doi.org/10.15252/emmm.201607199
Publication status	Published - May 2017

Keywords

antisense oligonucleotides
delivery
pre-clinical models
RNA therapy
toxicity

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Delivery is key: lessons learnt from developing splice‐switching antisense therapiesFinal published version, 1.67 MBLicence: CC BY

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Godfrey, C., Desviat, L. R., Smedsrød, B., Piétri-Rouxel, F., Denti, M. A., Disterer, P., Lorain, S., Nogales-Gadea, G., Sardone, V., Anwar, R., El Andaloussi, S., Lehto, T., Khoo, B., Brolin, C., van Roon-Mom, W. M. C., Goyenvalle, A., Aartsma-Rus, A., & Arechavala-Gomeza, V. (2017). Delivery is key: lessons learnt from developing splice-switching antisense therapies. EMBO Molecular Medicine, 9(5), 545-557. https://doi.org/10.15252/emmm.201607199

Godfrey, C, Desviat, LR, Smedsrød, B, Piétri-Rouxel, F, Denti, MA, Disterer, P, Lorain, S, Nogales-Gadea, G, Sardone, V, Anwar, R, El Andaloussi, S, Lehto, T, Khoo, B, Brolin, C, van Roon-Mom, WMC, Goyenvalle, A, Aartsma-Rus, A & Arechavala-Gomeza, V 2017, 'Delivery is key: lessons learnt from developing splice-switching antisense therapies', EMBO Molecular Medicine, vol. 9, no. 5, pp. 545-557. https://doi.org/10.15252/emmm.201607199

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abstract = "The use of splice-switching antisense therapy is highly promising, with a wealth of pre-clinical data and numerous clinical trials ongoing. Nevertheless, its potential to treat a variety of disorders has yet to be realized. The main obstacle impeding the clinical translation of this approach is the relatively poor delivery of antisense oligonucleotides to target tissues after systemic delivery. We are a group of researchers closely involved in the development of these therapies and would like to communicate our discussions concerning the validity of standard methodologies currently used in their pre-clinical development, the gaps in current knowledge and the pertinent challenges facing the field. We therefore make recommendations in order to focus future research efforts and facilitate a wider application of therapeutic antisense oligonucleotides.",

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AU - Disterer, Petra

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AU - Sardone, Valentina

AU - Anwar, Rayan

AU - El Andaloussi, Samir

AU - Lehto, Taavi

AU - Khoo, Bernard

AU - Brolin, Camilla

AU - van Roon-Mom, Willeke M.C.

AU - Goyenvalle, Aurélie

AU - Aartsma-Rus, Annemieke

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AB - The use of splice-switching antisense therapy is highly promising, with a wealth of pre-clinical data and numerous clinical trials ongoing. Nevertheless, its potential to treat a variety of disorders has yet to be realized. The main obstacle impeding the clinical translation of this approach is the relatively poor delivery of antisense oligonucleotides to target tissues after systemic delivery. We are a group of researchers closely involved in the development of these therapies and would like to communicate our discussions concerning the validity of standard methodologies currently used in their pre-clinical development, the gaps in current knowledge and the pertinent challenges facing the field. We therefore make recommendations in order to focus future research efforts and facilitate a wider application of therapeutic antisense oligonucleotides.

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KW - delivery

KW - pre-clinical models

KW - RNA therapy

KW - toxicity

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Delivery is key: lessons learnt from developing splice-switching antisense therapies

Abstract

Keywords

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