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EMBO Mol Med. 2017 May;9(5):545-557. doi: 10.15252/emmm.201607199.

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

Author information

1
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
2
Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain.
3
Department of Medical Biology, University of Tromsø, Tromsø, Norway.
4
UPMC, INSERM, UMRS 974, CNRS FRE 3617, Institut de Myologie, Paris, France.
5
Centre for Integrative Biology, University of Trento, Trento, Italy.
6
Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK.
7
Grup d'Investigació en Malalties Neuromusculars i Neuropediatriques, Institut d' Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona Barcelona, Spain.
8
Dubowitz Neuromuscular Centre and Developmental Neuroscience Programme, Institute of Child Health, University College London, London, UK.
9
Drug Discovery Informatics Lab, Qasemi-Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.
10
Drug Discovery and Development Laboratory, Institute of Applied Research, Galilee Society, Shefa-Amr, Israel.
11
Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
12
Institute of Technology, University of Tartu, Tartu, Estonia.
13
Centre for Neuroendocrinology, Division of Medicine, University College London, London, UK.
14
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
15
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
16
INSERM U1179, UFR des sciences de la santé, Université Versailles Saint Quentin, Montigny-le-Bretonneux, France.
17
Neuromuscular Disorders Group, BioCruces Health Research Institute, Barakaldo Bizkaia, Spain virginia.arechavalagomeza@osakidetza.eus.

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.

KEYWORDS:

RNA therapy; antisense oligonucleotides; delivery; pre‐clinical models; toxicity

PMID:
28289078
PMCID:
PMC5412803
DOI:
10.15252/emmm.201607199
[Indexed for MEDLINE]
Free PMC Article

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