Delivery of oligonucleotide-based therapeutics: challenges and opportunities

Suzan M. Hammond (1) , Annemieke M. Aartsma-Rus (2) , Sandra M. Alves (3) , Sven Even Finborud Borgos (4) , Ronald A.M. Buijsen (2) , Rob W.J. Collin (5) , Giuseppina Covello (6, 7) , Michela Alessandra Denti (7) , Lourdes Ruiz Desviat (8) , Lucía Echevarría (9) , Camilla Foged (10) , Gisela Gaina (11, 12) , Alejandro Garanto (5) , Aurélie T. Goyenvalle (13) , Magdalena Guzowska (14) , Irina Holodnuka (15) , David R. Jones (16) , Sabine Krause (17) , Taavi Lehto (18, 19) , Marisol Montolio (20) , W. van Roon-Mom (2) , Virginia Arechavala-Gomeza (21, 22)

1 University of Oxford
2 LUMC - Leiden University Medical Center
3 INSA - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
4 SINTEF Digital - Stiftelsen for INdustriell og TEknisk Forskning Digital [Trondheim]
5 Radboud University Medical Center [Nijmegen]
6 Unipd - Università degli Studi di Padova = University of Padua
7 UNITN - Università degli Studi di Trento = University of Trento
8 UAM - Universidad Autónoma de Madrid
9 SQY Therapeutics
10 UCPH - University of Copenhagen = Københavns Universitet
11 IVB - National Institute of Pathology Victor Babeş
12 UniBuc - University of Bucharest
13 END-ICAP - Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées
14 SGGW - Warsaw University of Life Sciences
15 RSU - Riga Stradins University
16 MHRA - Medicines and Healthcare Products Regulatory Agency
17 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
18 University of Tartu
19 Karolinska Institutet [Stockholm]
20 University of Barcelona
21 Biocruces Bizkaia Health Research Institute [Baracaldo]
22 Ikerbasque - Basque Foundation for Science

Nucleic acid-based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid-based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid-based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide-based therapeutics.

Mots clés: delivery; oligonucleotides; preclinical models; RNA therapeutics; safety

Domaines: Sciences du Vivant [q-bio]

Suzan M. Hammond, Annemieke M. Aartsma-Rus, Sandra M. Alves, Sven Even Finborud Borgos, Ronald A.M. Buijsen, et al.. Delivery of oligonucleotide-based therapeutics: challenges and opportunities. EMBO Molecular Medicine, 2021, 13 (4), ⟨10.15252/emmm.202013243⟩. ⟨hal-03218436⟩