RNAi Therapeutics: Promise, Speed and Challenge

RNA interference has the potential to one day enable physicians to turn off genes at will using small synthetic RNA molecules, and thus offer new therapies for both acute and chronic diseases, such as cancer and diabetes. The gene sequence based, ‘designer’ nature of these small RNAs allows drug leads to be discovered and optimised faster than ever, and lab-to-clinic speeds have accelerated to unprecedented levels. But there’s a challenging endgame ahead: unlocking safe and effective delivery methods that will enable RNAi and other oligonucleotide therapeutics to realise their full potential.

In 2002, the journal Science proclaimed RNAi the ‘breakthrough of the year,’ a declaration that came shortly after the discovery of RNAi in human cells. That advance sparked anticipation that RNAi could be used to silence the genes behind a wide range of devastating conditions – a list that included cancer, metabolic disorders, Huntington’s disease, Alzheimer’s disease and others. Because RNAi therapeutics are based on gene sequence, rather than protein structure, it became clear that any diseasecausing gene was back in play as a pharmaceutical target, regardless of how difficult prior efforts had proved to ‘drug’ the disease-causing protein.

It seems incredible today, but we have known about RNAi for less than two decades. The story of its first observations in 1990 by Rich Jorgensen in the course of his work with petunia pigmentation is already the stuff of folklore within the field. Eight years later, Andrew Fire and Craig Mello at the Carnegie Institution of Washington found the phenomenon was caused by long double-stranded RNA, which triggered the reduced expression of the target gene, a discovery that led to their 2006 Nobel Prize in Physiology or Medicine.