After 20 years, US regulators have finally approved the first RNA interference (RNAi)-based therapy, announced on August 10. The drug, called patisiran, targets a rare condition associated with impaired heart and nerve function and uses RNA interference to silence specific genes underlying the rare disease called hereditary transthyretin amyloidosis, which causes mutated forms of the transthyretin protein to accumulate in the body.
The discovery of RNAi over two decades ago led to hopes of finding breakthrough treatments for many incurable diseases. In fact, the Nobel Prize in Physiology or Medicine was awarded to Andrew Fire of Stanford University School of Medicine in California and Craig Mello of the University of Massachusetts Medical School in Worcester, the pioneers of RNAi. However, moving the gene therapy from bench to bedside has proven to be difficult and progress has been laden with setbacks.
One of the major difficulties hindering the use of this technology in the clinic has been figuring out how to deliver fragile RNA molecules to patients. Once created, RNA rapidly begins to degrade, therefore a significant challenge for researchers has been trying to prevent RNA degradation in the bloodstream as well as stopping the kidneys from filtering it out so that it can be spread to the tissues where it is needed.
The lack of progress in developing a delivery methods saw a plunge in share prices of gene therapy company in 2008 as investors began to lose confidence, and by 2010, many of the big pharmaceutical companies had abandoned RNAi technology altogether. Safety has also been a major concern and RNAi treatment has been potentially linked to the death of one patient during a clinical trial in 2016.
The drug was developed by Alnylam, a biopharmaceutical company based in Cambridge, Massachusetts, and patisiran was initially launched in 2002. Eventually, Alnylam was able to successfully encase RNA molecules in fatty nanoparticles and the RNA was also chemically modified to make it less susceptible to degradation. When injected into the bloodstream, the encapsulated RNAs seemed to accumulate in the kidneys and liver, which prompted Alnylam to target transthyretin, as it is produced mainly in the liver. In a clinical trial, 225 people with hereditary transthyretin amyloidosis with signs of nerve damage showed significant improvement in walking speed after receiving RNAi treatment compared to the placebo group in which walking speed declined.
Approval of the drug marks the inauguration of a new category of pharmaceuticals with many more applications purported to be in the pipeline. Alnylam is hoping to also target the brain and spinal cord, while Quark Pharmaceuticals of Fremont, California is also experimenting with RNAi therapies targeting kidney and eye diseases, and Arrowhead Pharmaceuticals of Pasadena, California, is developing RNAi treatments for cystic fibrosis.
In addition, further advances in RNAi delivery and the recent FDA approval may pave the way for other gene-editing therapies such as those based CRISPR–Cas9, which will also have to navigate a treacherous and lengthy path to the clinic.
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