RNAi therapeutics are disrupting disease

2018 saw a breakthrough in the field of RNA interference (RNAi), when the US FDA approved the first drug using this gene-silencing mechanism. Five years and five more approved drugs later, RNAi therapeutics are a proven class of medicines, and the potential for further innovation remains. “This is changing the practice of medicine,” says Kevin Fitzgerald, chief scientific officer of RNAi pioneer Alnylam Pharmaceuticals.

RNAi therapeutics are different because they target RNA, rather than the proteins targeted by 95% of conventional drugs¹. And because they work ‘upstream’ from protein-targeting medicines, RNAi therapeutics can treat conditions where the proteins were previously considered to be ‘undruggable’.

Not bad for a mechanism that was first observed in mammals in 2001. “It’s amazing how rapidly this has developed from basic research to a class of drugs that has achieved clinical success,” says Arthur Krieg, who studies oligonucleotide drugs at the RNA Therapeutics Institute at the University of Massachusetts in Cambridge.

RNAi-based therapeutic approaches are continually advancing, as are the methods to deliver the nucleotides that are foundational to them. Because of this progress, there are more diseases that RNAi drugs can potentially target, including common ailments such as hypertension and Alzheimer’s disease.

The therapeutic hypothesis of using RNAi is particularly compelling in cardiovascular disease, the world’s leading cause of death^2. And in Alzheimer’s disease, despite recent advances and drug approvals, the field is still revealing its potential.

The science of silencing

The inspiration for RNAi therapeutics comes from a naturally occurring cellular defence mechanism against viral infection that relies on small interfering RNAs (siRNAs). Each siRNA is a complementary sequence to a key piece of viral RNA. siRNA circulates within a cell as part of a protein complex; if it finds a match, the protein complex destroys the viral RNA, preventing protein synthesis, the final stage of gene expression. As a result, gene expression is ‘silenced’.

In the early 2000s, researchers hypothesized that the RNAi process could be harnessed to target any single-stranded RNA in a cell, including the cell’s own messenger RNA (mRNA). They proposed synthesizing siRNAs with specific genetic sequences and introducing them into tissues where gene expression takes place.

“RNAi is tapping into an existing mechanism,” says David Corey, a biochemist at UT Southwestern Medical Center in Dallas. “Like sailing with the wind at your back, nature is doing the work for you.”

The clinical applications are obvious. Synthetic strands of siRNA can be designed to complement any target mRNA, Corey explains, giving RNAi-based medicines the potential to silence essentially any gene, selectively reducing the amount of a protein the body can produce. As the gene silencing process is catalytic — that is, a single siRNA can degrade many mRNAs — one dose of an RNAi therapeutic can silence a gene for an extended period³, requiring fewer doses than other classes of medicines.

RNAi can also treat diseases where the protein does not have an appropriate binding site for conventional therapeutic agents. “RNAi is good for targets where a small molecule isn’t an option,” says Corey. “Rather than competing with small-molecule drugs, you can look for targets that are hard or impossible for them to reach.”

RNAi therapeutics fit within a broader category of genetic medicines that employ DNA and RNA to treat disease, including CRISPR-based medicines and mRNA vaccines. Unlike some other genetic medicine technologies, RNAi is firmly established, with a strong track record of safety and efficacy in the clinic. There are six approved RNAi therapeutics — including five discovered at Alnylam — for conditions ranging from a rare form of amyloidosis to hypercholesterolaemia.

Each type of genetic medicine has key features and benefits. Fitzgerald sees the temporary nature of RNAi, compared with making permanent edits to genes, as an important safety feature. “With RNAi, we can titrate the dose, and it wears off over time,” says Fitzgerald. “Every patient is different, and may respond differently to therapy. The ability to adjust dosing while still delivering therapeutic benefits with infrequent administration makes RNAi therapeutics very desirable for doctors and patients.” He believes RNAi technology will disrupt medicine in the same way that monoclonal antibodies did when they were invented, changing treatment paradigms across several therapeutic areas.

An expanding treatment landscape

The first commercially available RNAi therapeutic — discovered and developed at Alnylam — was approved for adults in 2018 for the treatment of a rare disease called hereditary transthyretin (ATTR) amyloidosis with polyneuropathy. Like many rare diseases, hereditary ATTR is monogenic. A mutation in the TTR gene results in a misfolded protein that overwhelms the body’s capacity to clear it. The misfolded protein clogs up organs and can cause a wide range of symptoms, including nerve pain and numbness, weight loss, fatigue and muscle weakness. ATTR amyloidosis is often fatal. Although the RNAi therapeutic doesn’t stop production of all the mutant protein, it slows it enough to allow the body to clear the misfolded protein, reducing symptoms.

Fitzgerald says ATTR was the “ideal case” for RNAi. TTR is highly expressed in the liver, which proved the most advantageous site for delivery of the first RNAi therapeutics. RNA is big and covered with negative charges, which poses a challenge when crossing cell membranes. But the liver likes to take up large molecules, and Alnylam initially used lipid nanoparticles — later applied in the delivery of mRNA COVID-19 vaccines — to get them into the right cells. Alnylam researchers also discovered that they could conjugate siRNAs to a sugar molecule called GalNAc, which binds to a receptor abundantly expressed on liver cells, showing a potential path forward for delivery to other tissue types.

The first three approved RNAi drugs — all discovered and developed at Alnylam — were for rare, monogenic diseases with targets expressed in the liver. As confidence in the technology grew, however, focus expanded to common illnesses such as hypercholesterolaemia and hypertension, where the underlying causes are more complicated. And researchers are now unlocking new tissues for RNAi with advances in delivery technology, including new conjugates.

Alnylam has a candidate in a phase I clinical trial in early-onset Alzheimer’s disease. The investigational RNAi therapeutic targets mutant versions of amyloid precursor protein (APP), which are closely associated with familial cases of both Alzheimer’s and cerebral amyloid angiopathy.

“The concept isn’t too different from ATTR,” says Fitzgerald. “We aim to lower the amount of APP to the point where we shift the balance back to clearance.”

Krieg says that RNAi could be a fundamentally different approach to treating many neurological diseases. And, he adds, there are hints that RNAi may be useful against other common diseases⁴. “It’s going to be really exciting, seeing it evolve over time.”