Huntington’s disease is one of more than 40 diseases known to be caused by a genetic glitch in which a trio of nucleotides—CAG in Huntington’s—is erroneously repeated. It’s as if someone using the genetic equivalent of a word processor copied the sequence and then repeatedly pasted it: CAGCAGCAGCAG.
Scientists have long believed that the number of these triplet repeats determines the age at which a person will begin experiencing the symptoms of Huntington’s, but some examples suggest otherwise. One person with 40 repeats might develop the disease in mid-life. Another might not know they have Huntington’s until they are elderly.
“People knew about this, but they didn’t know why it happens,” says Nessan Bermingham, cofounder and CEO of a new company, Triplet Therapeutics, that thinks it has the answer: “The repeats drive the disease, but not the repeats you are born with.” It’s when the repeats grow longer with age that things get dicey, Bermingham explains. He says Triplet has landed on the variable that explains why repeats grow uncontrollably in some people but not others.
Now, the startup is emerging from stealth mode and announcing a $10 million seed investment from Atlas Venture and a $49 million series A financing led by MPM Capital and Pfizer Ventures. Triplet’s goal is to develop antisense oligonucleotide and RNA interference (RNAi) drugs that decrease the expression of proteins that increase the risk of triplet repeats expanding to dangerous lengths. The strategy, if it works, could be used to treat, or at least stall, the progression of dozens of conditions that geneticists classify as triplet-repeat diseases.
It’s not Bermingham’s first rodeo in genetic therapy. He was formerly CEO of the CRISPR gene-editing company Intellia Therapeutics. Last year, while working as a partner at Atlas Ventures, he founded both Triplet and Korro Bio, which is developing antisense oligonucleotide-based RNA editing therapies.
Brain biopsies from people with Huntington’s disease show that in some areas of the brain, such as the cerebellum, the number of repeats is similar to what a person was born with. But in other areas of the brain, such as the cortex, the number of repeats may have exploded from 40 to hundreds, or even up to nearly 1,000.
Bermingham says three recent genome-wide association studies—for myotonic dystrophy, spinocerebellar ataxias, and Huntington’s disease—all point to genetic variants in the DNA damage response (DDR) pathway as the culprits for accelerating the development of these diseases.
Under normal circumstances the DDR is our friend, instructing a large number of proteins to coordinate the maintenance and repair of our genome. But for someone with a triplet-repeat disorder, the DDR can be a liability. When the double helix of DNA is unwound during transcription, sometimes triplet-repeat sequences flop out and form a loop. When DDR proteins come in to straighten out the mess, the repair crew can get confused by the redundant sequence and expand the number of triplet repeats.
“So by preventing that repair from happening, you can prevent expansion and delay or prevent the onset of the disease,” Bermingham says. And if the startup can get it to work for one triplet-repeat disease, then there’s a decent chance that it will work for others too.
Bermingham won’t disclose which target in the DDR pathway Triplet is focused on, but he says the firm has tested the concept in mice and shown that reducing levels of certain DDR proteins halts triplet-repeat expansion.
Of course, the DDR is not entirely dispensable. But out of the nearly 100 genes involved in making proteins for the DDR, Triplet is looking at a small number that appear safe to knock down. Furthermore, Triplet’s drugs won’t be for body-wide distribution. They will be designed for injection or delivery to specific organs, such as the brain, in the case of Huntington’s, and the muscle, in the case of myotonic dystrophy.
Bermingham says Triplet’s funding should carry it into the second half of 2021—and hopefully into a clinical trial by that time.
“We’ve taken the company from a sheet of paper just over a year ago to having multiple leads in non-human primate studies,” Bermingham says. And although it could be some years before he has evidence that the experimental therapies work in humans, his firm’s preclinical progress is a testament to today’s rapid pace of antisense oligonucleotide and RNAi drug discovery.