title: Delivery is key: lessons learnt from developing splice-switching antisense therapies.
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.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Godfrey
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Lourdes R
authors.initials: LR
authors.lastname: Desviat
authors.affiliation: Department of Medical Biology, University of Tromsø, Tromsø, Norway.
authors.forename: Bård
authors.initials: B
authors.lastname: Smedsrød
authors.affiliation: UPMC, INSERM, UMRS 974, CNRS FRE 3617, Institut de Myologie, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Piétri-Rouxel
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Michela A
authors.initials: MA
authors.lastname: Denti
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK.
authors.forename: Petra
authors.initials: P
authors.lastname: Disterer
authors.affiliation: UPMC, INSERM, UMRS 974, CNRS FRE 3617, Institut de Myologie, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lorain
authors.affiliation: Grup d'Investigació en Malalties Neuromusculars i Neuropediatriques, Institut d' Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona Barcelona, Spain.
authors.forename: Gisela
authors.initials: G
authors.lastname: Nogales-Gadea
authors.affiliation: Dubowitz Neuromuscular Centre and Developmental Neuroscience Programme, Institute of Child Health, University College London, London, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sardone
authors.affiliation: Drug Discovery Informatics Lab, Qasemi-Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.|Drug Discovery and Development Laboratory, Institute of Applied Research, Galilee Society, Shefa-Amr, Israel.
authors.forename: Rayan
authors.initials: R
authors.lastname: Anwar
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.|Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Samir
authors.initials: S
authors.lastname: El Andaloussi
authors.affiliation: Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.|Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Taavi
authors.initials: T
authors.lastname: Lehto
authors.affiliation: Centre for Neuroendocrinology, Division of Medicine, University College London, London, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Khoo
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Brolin
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Willeke Mc
authors.initials: WM
authors.lastname: van Roon-Mom
authors.affiliation: INSERM U1179, UFR des sciences de la santé, Université Versailles Saint Quentin, Montigny-le-Bretonneux, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Goyenvalle
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.affiliation: Neuromuscular Disorders Group, BioCruces Health Research Institute, Barakaldo Bizkaia, Spain virginia.arechavalagomeza@osakidetza.eus.
authors.forename: Virginia
authors.identifier: 0000-0001-7703-3255
authors.initials: V
authors.lastname: Arechavala-Gomeza
mesh_terms: D000818:Animals; D004333:Drug Administration Routes; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D012326:RNA Splicing / Q000187:drug effects
chemical_list: D016376:Oligonucleotides, Antisense
keywords: RNA therapy; antisense oligonucleotides; delivery; pre‐clinical models; toxicity