What unifies Huntington’s, spinocerebellar ataxia and myotonic dystrophy? Ness Bermingham’s new startup looks to drug that – Endpoints News

Posted: December 18, 2019 at 11:41 pm

Ness Berminghams latest venture brings throwbacks to some of his earliest work in biopharma. Part of his PhD work at Imperial College London revolved around triplet repeat disorders, a group of 40 or so genetic diseases characterized by the repetition and expansion of specific trinucleotide sequences. During his early years at Atlas Venture way before he became known as a co-founder of pioneering CRISPR player Intellia he helped create a biotech, Prestwick Pharmaceuticals, that created a Huntingtons drug dubbed tetrabenazine.

Back then and until very recently even though Huntingtons and other diseases such as spinocerebellar ataxia and myotonic dystrophy fell under the same umbrella, they were construed as separate afflictions. A potentially unifying theory, as it turned out, lay in one question: Why dont patients born with the same repeats always begin to see symptoms at the same age?

For quite some time people had known that there are these genetic modifiers that really seem to profoundly impact these diseases and the onset and progression of these diseases, Bermingham told Endpoints News.

Triplet Therapeutics, which is doing the rounds today with $59 million in launch cash from Atlas, MPM Capital and Pfizer Ventures, believes the key to that mechanism is the DNA damage response pathway.

The DNA damage response pathway, or DDR, is a crucial way for cells to repair genetic material. But in patients with repeat expansion disorders, when their DDR machine goes in to fix the kinks during DNA replication, they also insert multiple repeating sequences in turn blowing up the size of the DNA so much that its more prone to damage, creating a snowball effect, according to Bermingham.

Out of about 100 genes involved in the DDR pathway, Triplet has identified a couple key drivers that they can target to stop the insertion of repeats, thereby holding the disease at bay.

That has allowed to shift their thinking from a disease standpoint to a tissue standpoint, Bermingham said, and the first tissue they will go after is the brain: Huntingtons, multiple subtypes of spinocerebellar ataxia, dentatorubralpallidoluysian atrophy, myotonic dystrophy, and so on.

As you move from tissue to tissue, it opens up different drugs of different formulations that hit the same target, he said.

Unlike at Korro Bio, the RNA editing outfit Bermingham has recently unveiled as executive chairman, Triplet is not looking to new tools. Rather, the goal is to home in on a fundamental driver of disease upstream of what rivals like Roche/Ionis and Wave are knocking out in Huntingtons.

The candidates they are now testing in non-human primates for CNS disorders are antisense oligonucleotides, but for other tissues such as muscles, the eye or even the kidney, they also plan to use small interfering RNA. These tools were chosen as they provide more specific targeting and less safety issues than, say, small molecules, Bermingham said.

The CEO added that using ASO and siRNA has allowed his team of 29 to move quickly, ready to enter the clinic within two years the runway that the Series A (also featuring Invus, Partners Innovation Fund and Alexandria Venture Investments) is providing. In the process hes looking to grow the company to somewhere between 45 to 60.

Currently helping Bermingham run the operations are some seasoned execs in the space: Irina Antonijevic, SVP of development, previously led translational medicine and early development at Wave; Brian Bettencourt, SVP of computational biology & statistics, specialized in modeling and design of oligonucleotide and mRNA at Translate Bio; David Morrissey, SVP of technology, and Peter Blalek, head of translational sciences, are both old colleagues from Intellia; Head of pharmacology Pei Ge led the Huntingtons program at Alnylam before moving to Ironwood; Eric Sullivan, CFO, was formerly of Gemini Therapeutics and bluebird bio; and Jeffrey Cerio, general counsel, has served at Moderna.

Shinichiro Fuse of MPM and Laszlo Kiss of Pfizer Ventures are joining the board, chaired by Atlas partner Jean-Franois Formela, alongside Douglas Kerr, chief development officer at Generation Bio. Then theres the scientific advisory board comprising three academic experts, including Vanessa Wheeler at Massachusetts General Hospital, who happened to be a PhD mate of Berminghams.

Ramping up would mean spending the majority of his time with Triplet at the new Kendall Square offices they are moving into in January, slightly detached from Atlas which he rejoined as venture partner less than two years ago in the wake of his exit from the helm of Intellia.

Its my intent to stay here and see this company through, he said. Im trained as a human geneticist originally, and then further specialized down to molecular biology. So this is absolutely in my sweet spot.

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What unifies Huntington's, spinocerebellar ataxia and myotonic dystrophy? Ness Bermingham's new startup looks to drug that - Endpoints News

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