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.
Highlights
The use of splice-switching antisense therapy is highly promising, with a wealth of pre-clinical data and numerous clinical trials ongoing
Antisense oligonucleotides as RNA-modulating therapeutics are highly specific and easy to design making them attractive sequencespecific drugs and their role in the pipeline towards “personalized therapy” has made them a hot topic of research in recent years
The poster boy for this development has been Duchenne muscular dystrophy (DMD) and stakeholders representing other rare disorders have followed the advances in the development of these Antisense oligonucleotides (AONs) closely
Summary
The use of splice-switching antisense therapy is highly promising, with a wealth of pre-clinical data and numerous clinical trials ongoing. In either scenario, to be able to rationally programme the delivery, including cellular association, uptake and trafficking of AONs, further basic research is required to fully characterize and potentially exploit these complex events Both in vitro and in vivo models are required for pre-clinical testing of new AONs. It is generally accepted that while in vitro models provide data on the AON mechanism of action and efficacy, in vivo models are better suited to assess the delivery of the compound. Non-human primates might be envisaged as a suitable species for testing of the effects of AONs designed for the treatment of human disease, as their genomic sequences are closer to those of humans, as is their metabolism, but this needs to be balanced against the ethical issues of using such animals and the increased expenses incurred Both cell culture and animal models are complementary and indispensable for the development of AON-based therapies and they should be used with foreknowledge of their limitations
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