The era of genetic medicine has arrived. As scientists continue to unravel the mysteries of humanity’s genetic blueprint, their discoveries are driving the emergence of new types of therapies such as gene editing and gene replacement, which target the roots of disease. But what does this mean for patients and physicians today? Genetic medicine technologies vary widely in their maturity, but one is already firmly established and poised to disrupt the treatment of disease for millions of patients: RNA interference (RNAi) therapeutics.
This approach silences genes—and disease—by harnessing the Nobel Prize-winning discovery of RNAi. The world’s first RNAi therapeutic, discovered and developed by Alnylam Pharmaceuticals, was approved by the US Food and Drug Administration (FDA) in 2018, and five more have been approved since then.
“It’s amazing how rapidly this has developed from basic research to a class of drugs,” says Art Krieg, from the RNA Therapeutics Institute at the University of Massachusetts. “It’s going to be really exciting, seeing it evolve over time.”
RNAi therapeutics are already in use by tens of thousands of patients around the world, with an encouraging track record of safety and efficacy. This puts them a step ahead of many other genetic medicines. And now, RNAi therapeutics have the potential to have an even larger impact as scientists apply the RNAi approach to a growing list of more common conditions. Here’s everything you need to know about this innovative class of medicines.
How do RNAi therapeutics work?
RNAi therapeutics harness the natural process of RNAi that occurs in every cell in the body. Genes contain the instructions for making proteins, the ‘workers’ in the biochemistry of life that are responsible for almost all cellular and body functions. Cells use RNAi as a dimmer switch on genes, turning down the production of specific proteins. By mimicking this system, developers of RNAi therapeutics can direct the process to silence genes that cause or contribute to disease.
David Corey, a biochemist at UT Southwestern Medical Center in Dallas, admires RNAi therapeutics’ ability to tap into this natural process. “It’s like sailing with the wind at your back,” he says. “Nature is doing the work for you.”
How do they differ from standard medicines?
RNAi therapeutics act ‘upstream’ compared to most other medicines. Instead of targeting proteins involved in disease, they disrupt the production of unwanted proteins before they are made. If a disease is a leaking tap, then RNAi fixes the leak rather than mopping the floor afterwards, like standard medicines. The pioneers behind RNAi believe this approach could be used to silence virtually any gene. This raises the hope that RNAi therapeutics could be applied to slow, halt or reverse the progression of a wide range of devastating diseases, including conditions without any treatment options.
RNAi therapeutics are also long-lasting. Many medicines must be taken daily, but a single dose of an RNAi therapeutic can last for months. “Instead of relying on the patient to take over 300 pills a year, you can give a couple of injections,” says Kausik Ray, a cardiologist at Imperial College London who has worked on the development and testing of RNAi drugs.
What separates RNAi therapeutics from other genetic medicines?
Genetic medicine encompasses a range of approaches, all building on a growing understanding of the role that genes play in disease. Each technology has its own features and benefits. In contrast to some other genetic medicines such as CRISPR-based gene editing, RNAi therapeutics do not alter the genes (DNA) within cells. Instead, they target and degrade messenger RNA (mRNA), molecules that carry the instructions from genes to a cell’s protein-producing machinery. Kevin Fitzgerald, chief scientific officer of Alnylam Pharmaceuticals, sees this as an important safety feature.
“RNAi therapeutics avoid the safety concerns that come along with making permanent changes to DNA while still delivering therapeutic benefits with infrequent administration,” he explains.
RNAi therapeutics have also been more extensively tested than some other genetic medicine technologies. Investigational RNAi therapeutics have been in the clinic for nearly two decades, and there are six approved products available to patients, five of them discovered by Alnylam.
What diseases can RNAi therapeutics treat?
The first few RNAi therapeutics were approved by the FDA to treat rare genetic diseases. As confidence in the technology has grown, focus has expanded to common conditions such as high cholesterol and high blood pressure, which have more complex underlying causes. In fact, RNAi therapeutics have the potential to disrupt the way that multiple cardiovascular disease risk factors are treated.
Another exciting new area of focus for RNAi researchers is neurodegenerative disease. Alnylam scientists recently developed an approach for delivering RNAi therapeutics to cells of the central nervous system, and now they are exploring RNAi for the treatment of diseases ranging from Huntington’s to Alzheimer’s.
“I’m particularly excited about our work on neurodegenerative diseases because there are so few effective treatments for them,” says Fitzgerald. “My own family has been affected by Parkinson’s disease, so this is personal. RNAi therapeutics represent hope for millions of patients and their families, including my own.”
To learn more about the science behind Alnylam’s pioneering RNAi therapeutics, click here.