Huntington’s disease drug research has focused mainly on the genetic roots of the rare neurodegenerative disorder. Triplet Therapeutics is taking a different tack by targeting a DNA repair mechanism gone awry, an approach that CEO Nessan Bermingham says could offer a better way to treat that disease and potentially dozens of others.
Cambridge, MA-based Triplet now has $49 million in funding to advance its work. The startup’s Series A round of funding, announced Tuesday, was led by MPM Capital and Pfizer Ventures. The new cash follows $10 million in seed financing Triplet received from Atlas Venture last year when the company was founded. Bermingham is a venture partner at Atlas and a Triplet co-founder.
Huntington’s stems from a mutation to the gene that produces huntingtin, a protein thought to play an important role in neuron function. The disease is a trinucleotide repeat disorder, one of a group of diseases in which a sequence of DNA building blocks repeats multiple times, resulting in a version of a protein—in this case, huntingtin—that’s toxic to brain cells. Bermingham contends that addressing the cause of this repeating code, also known as repeat expansions, is what’s key.
“We believe, if you’re going to treat these patients, you have to go to the fundamental driver of the disease itself,” Bermingham says. “It’s not the gene. It’s the mechanism that drives expansion of the gene.”
The repeat expansions create loops in the DNA that resemble hairpins, Bermingham says. It’s at this point that the DNA repair mechanism comes into play. Cells have processes to identify and correct DNA damage. But Bermingham, a co-founder and former CEO of gene-editing biotech Intellia Therapeutics (NASDAQ: NTLA), says that when these DNA damage responders encounter the hairpins, the attempted fix instead drives further repeat expansions. It’s similar to the way a jammed computer key endlessly types the same letter. Triplet is developing drugs to stop the repeats, which Bermingham says could potentially stop the progress, or even the onset, of Huntington’s.
Triplet’s work is based on a growing body of research that points to DNA damage response as a driving factor in repeat expansion. These repeats are also characteristic of other rare disorders, including myotonic dystrophy, Fragile X syndrome, and spinocerebellar ataxia, findings that come from analysis of human genetic data. Because this expansion mechanism is shared by more than 40 rare diseases, Bermingham says Triplet’s approach could potentially apply to all diseases that involve the mechanism.
There are other companies pursuing potential Huntington’s treatments. An Ionis Pharmaceuticals (NASDAQ: IONS) drug intended to reduce the production of the mutant huntingtin protein is being developed under a partnership with Roche. Wave Life Sciences (NASDAQ: WVE) is also targeting huntingtin, and has said it expects to report preliminary data from Phase 1b/2a studies by the end of this year. Voyager Therapeutics (NASDAQ: VYGR) and uniQure (NASDAQ: QURE) are developing gene therapies to treat the disease.
Triplet is developing two types of drugs: antisense oligonucleotides and small interfering RNA compounds. Bermingham says these drugs are intended to stop parts of the DNA damage response pathway that drive repeat expansion. He adds that the effect is precise, selectively targeting only the parts of the pathway involved in the repeats. The ability for the repair mechanism to perform other DNA fixes remains intact.
So far, Triplet has tested its approach in monkeys. Triplet says it will use the new capital for the additional research needed to support an application to test the technology in humans, as well as for natural history studies, which track a group of people at risk of developing a disease as a way of informing clinical trial plans. Bermingham declined to provide an estimate of when Triplet expects to start tests in humans.
Besides Atlas, other investors in Triplet’s latest financing include Invus, Partners Innovation Fund, and Alexandria Venture Investments.