TTR amyloidosis is a rare hereditary disease characterized by abnormal production of a protein called transthyretin, or TTR, which is responsible for shuttling the thyroid hormone thyroxine (T4) and retinol (an animal form of vitamin A) around the body. Hence, the name transthyretin: transports thyroxine and retinol. The defective version of the protein is unable to perform its task and ends up getting lodged in the nerves and heart, forming insoluble clumps known as amyloid deposits.
In the beginning, this kind of damage may lead to loss of physical sensation, and some patients even become bedridden. As the disease progresses, the amyloid deposits may damage the nerves that are responsible for processes such as digestion, giving rise to a multitude of symptoms, including diarrhea, vomiting, constipation, and low blood pressure.
Transthyretin is produced in the liver, so in 1990, physicians began offering patients with the disease liver transplants. However, this strategy wasn’t terribly effective. Liver transplants are difficult to come by, and for many patients this approach fails to produce the intended results. In recent years, researchers have developed two stabilizing drugs–diflunisal and tafimidis, which are intended to keep the abnormal TTR from misfolding. Both drugs do seem to slow the progression of the disease, but neither constitute a cure.
According to an article published by NOVA Next, researchers are now working to develop a class of medicines aimed at accomplishing what no other therapies have before: silencing the TTR gene. Rather than merely treating the symptoms of TTR amyloidosis, this therapy will tackle the root of the problem by blocking production of the problematic protein. In 1998, Andrew Fire and Craig C. Mello took a major step towards this approach while working with the nematode worm C. elegans. They discovered the double-stranded RNA could trigger gene silencing. They called this process RNA interference, or RNAi. The pair won the 2006 Nobel Prize in Physiology or Medicine for their innovative work.
In the following years, researchers began to uncover the mechanisms behind this promising process. In order to produce a protein, cells require messenger RNA, which carries instructions for the production of proteins to the ribosomes in a cell’s cytoplasm. Double-stranded RNA, however, disrupts this process. Upon encountering dsRNA, enzymes called dicers slice the dsRNA into small chunks around 20 nucleotides long. Next, these double-stranded bits, known as small interfering RNAs (siRNAs), bind to a class of proteins called Argonautes. The Argonautes can then seek out mRNA with a complementary base sequence and slice these mRNA strands, rendering them useless. Without mRNA, a cell cannot produce proteins. The siRNAs have the ability to bind to Argonautes multiple times, so a single siRNA molecule can effectively destroy hundreds of mRNA molecules within a cell.
Conventional drugs attack a protein by binding to them, but many proteins lack a good active site. Out of more than 100,000 proteins that the body is capable of producing, researchers have only been able to target a few hundred. RNAi offers a single method to block all of them. In 2002, Philip Sharp, a Nobel laureate and molecular biologist at the Massachusetts Institute of Technology in Cambridge, teamed up with scientists involved in the early development stages of RNAi to launch Alnylam, the first company aimed at developing RNAi therapies. John Maraganore, CEO of Alnylam, says, “With RNAi we can stop a flood by turning off a faucet. Small molecules can only mop up the floor.”
In July 2010, Alnylam launched the first human study to test the efficacy of its therapy for TTR amyloidosis, an siRNA wrapped in a lipid nanoparticle. Participants received a single dose, and the initial results were promising. In 2012, the company launched another study to test the safety of the drug and its impact on TTR production. One dose of the medicine ended up inhibiting TTR production by as much as 94%. Last winter, Alnylam launched a phase III clinical trial. The 18-month study is aimed at examining whether the medication has any impact on the participants’ nerve function. One group will receive a saline solution and the other group will be administered the drug, called partisiran. Because partisiran and other RNAi therapies depend on lipid nanoparticles, they must be administered via an IV.
Partisiran is the first RNAi therapy to enter a phase III clinical trial and may become the first RNAi therapy on the market. But RNAi offers hope for developing therapies that extend far beyond amyloidosis. Alnylam is currently working on developing therapies for seven other diseases, including hemophilia and high cholesterol. And other companies are developing siRNAs to treat everything from ebola to liver cancer. However, even if partisiran succeeds, the drug will not be widely available for the next several years. Alnylam won’t have the results of the phase III trial until 2017.