RNA interferenceFire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC · Nature, 1998
The paper that discovered RNA interference. Fire and Mello showed that double stranded RNA, not single strands, is the potent trigger that silences a matching gene in the worm C. elegans. The work revealed a natural gene silencing pathway, earned the 2006 Nobel Prize in Physiology or Medicine, and laid the foundation for every siRNA medicine that followed.
RNA interferenceElbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T · Nature, 2001
The study that made RNA interference usable in human cells. Long double stranded RNA triggers a toxic immune response in mammalian cells, but this work showed that short 21 nucleotide duplexes silence a target gene cleanly without setting off that alarm. It defined the size and shape of the modern synthetic siRNA and opened the door to human therapeutics.
DeliveryNair JK, Willoughby JLS, Chan A, Charisse K, Alam MR, Wang Q, et al. · Journal of the American Chemical Society, 2014
The delivery breakthrough that made siRNA drugs practical. Attaching a three armed GalNAc sugar to an siRNA lets liver cells take it up efficiently after a simple injection under the skin, giving durable gene silencing at low doses. GalNAc conjugation is now the backbone of most approved and clinical siRNA medicines.
AntisenseBennett CF, Swayze EE · Annual Review of Pharmacology and Toxicology, 2010
A foundational review of how antisense oligonucleotides work as medicines. It lays out the mechanisms by which an ASO can silence, block or reshape a target RNA, the chemistries that make them stable enough to use, and the pharmacology of the platform. It remains a standard starting point for understanding the ASO field.
ClinicalFinkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. · New England Journal of Medicine, 2017
The trial that proved a splice switching antisense oligonucleotide could change the course of a fatal disease. Nusinersen redirects the splicing of the SMN2 gene to restore a working protein in infants with spinal muscular atrophy, dramatically improving survival and motor milestones. It became one of the first widely approved ASO drugs and a landmark for the whole modality.
ReviewsSetten RL, Rossi JJ, Han S · Nature Reviews Drug Discovery, 2019
A comprehensive review of RNA interference as a drug class, written as the first siRNA medicines reached the clinic. It covers design, chemical modification, delivery beyond the liver and the clinical pipeline, giving a clear map of where the field stood and the problems still to solve. A useful orientation for anyone entering siRNA drug development.
ChemistryWan WB, Seth PP · Journal of Medicinal Chemistry, 2016
A detailed survey of the chemical modifications that turn a fragile strand into a medicine. It compares backbone changes, two prime sugar modifications, bicyclic nucleic acids and conjugation strategies, and explains how each affects stability, affinity, potency and safety. An essential reference for designing the modification pattern of an oligonucleotide.
SynthesisBeaucage SL, Caruthers MH · Tetrahedron Letters, 1981
The chemistry that lets any oligonucleotide be made to order. Beaucage and Caruthers introduced the phosphoramidite method, a fast and reliable way to build DNA one base at a time on a solid support. It became the universal standard for oligonucleotide synthesis and underpins every custom oligo ordered today, including those made by Syngenis.
ReviewsCrooke ST, Witztum JL, Bennett CF, Baker BF · Cell Metabolism, 2018
A broad review of drugging RNA rather than protein. It brings together antisense oligonucleotides, siRNA and related approaches, explaining the shared logic of recognising a target sequence and the pharmacology, safety and delivery challenges common to all of them. A good single reference for the RNA targeted drug landscape.
AptamersEllington AD, Szostak JW · Nature, 1990
The paper that introduced aptamers. Ellington and Szostak showed that specific RNA molecules can be selected from a vast random library to bind a chosen target, coining the term aptamer. This in vitro selection idea, later called SELEX, underpins aptamer based diagnostics and therapeutics, including the Syngenis aptamer diagnostics pipeline.