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In 2010, everything changed for aspiring lawyer Sonia Vallabh. Her mother fell suddenly ill and passed away within a year, without a diagnosis. “She lost abilities almost on a day-to-day, week-to-week basis,” Vallabh said. After her mother passed away, Vallabh searched for answers, finding herself shocked at every turn. Vallabh’s mother had genetic prion disease, a rare and devastating rapid dementia caused by the templated misfolding and accumulation of a specific protein, called the prion protein, in the brain. Vallabh discovered that she had inherited the single genetic mutation that caused her mother’s death, making her extremely likely to experience the same disease. Instead of allowing it to rule her life, Vallabh decided to find a way to take her genetics into her own hands—Vallabh and her husband Eric Minikel, then a transportation engineer, completely pivoted their careers, enrolling in doctoral programs to become scientific researchers at Harvard University.
Vallabh’s mission led her to assemble a team of collaborators united by a shared goal, which Vallabh called her “North Star”: developing a therapy for prion disease within their lifetimes. “This collaboration is really a story of having a superb team oriented around the same goal, which allowed us to move more quickly than any of us had hoped,” Vallabh said. Indeed, Vallabh wasted no time assembling a team, and the time from beginning the collaboration to publishing the paper that detailed their results was only two years. Among those Vallabh recruited was Jonathan Weissman, a scientist at the Whitehead Institute for Biochemical Research whose expertise in gene silencing technology would prove crucial to their work. “It was a compelling mission. Sonia and Eric had brought together all the necessary people. […] It was a full package,” Weissman said.
Weissman’s lab has had a long-term interest in tools controlling gene expression; one such method uses CRISPR technology that, while powerful, is too difficult to effectively deliver information to all or most of the neurons in the adult human brain. The team needed both a smaller tool for permanently silencing the production of prion protein and a better means to deliver it to the cells that need it.
Through a series of engineering innovations, the Weissman Lab landed on a new epigenetic editing tool: the Coupled Histone tail for Autoinhibition Release of Methyltransferase, or CHARM for short. CHARM is small enough to fit within a single viral vector. They also engineered a self-silencing mechanism that could theoretically enable a CHARM therapy to silence itself after silencing its target gene, potentially enhancing the safety profile of the therapy. Meanwhile, Ben Deverman, a viral vector expert, has led the charge on the major challenge of delivery to the brain.
Ultimately, thanks to the synergy between an efficient viral vector and CHARM’s small size, an eighty percent reduction in prion protein expression in the brain was observed—an exciting finding that has made the team optimistic about CHARM’s applications. “There’s reason to hope that if we can get to people early enough, it could be an effective therapy across the different subtypes of prion disease,” Vallabh said. As she continues to work on the next steps of CHARM development, Vallabh shows no signs of slowing down. With CHARM showing such promising results, Vallabh’s North Star may soon be within reach.