In the case of another historic first in the world of healthcare, this summer saw the first US and EU regulatory approvals for an RNA interference (RNAi) therapeutic, in the form of Alnylam’s Onpattro (patisiran). The drug, given as an infusion, was approved to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. A rare and often fatal disease, hAATR is characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart, and other organs. Up until this approval, the American College of Cardiology’s recommendations for treatment were merely supportive care and clinical trials, pointing to the level of unmet need for this patient population[1].
Still, it has been anything but smooth sailing for Onpattro, nor for the field of RNA-based medicines. Like gene therapy, it has seen an earlier wave of enthusiasm come crashing down in the wake of technical challenges and safety issues. While Onpattro will not be a panacea to all the known issues, it is important to note where and how it has succeeded where others have failed and to understand what it means for other candidates in the pipeline.
How it works
To understand how RNAi works, transport yourself to your high school biology class where you learned about the “central dogma” theory that explains the relationship between DNA, RNA and proteins – that DNA in the nucleus forms genes which are the template for transcription to RNA, which in turn is the template for translation to proteins. Those proteins then serve as a central player in most biological systems. In individuals without hAATR, the liver produces the TTR protein, used to transport vitamin A and a thyroid-binding protein in the body. Patients with hATTR have a mutation in the gene for TTR, which leads to the creation of a defective and unstable TTR protein. Onpattro binds to the mutated mRNA sequence that causes the defective protein, and cuts out that sequence, effectively halting the production of the misfolded and defective protein[2]. Of note, this approach targets the upstream