Zach Hoffman with his father Paul and son Henry. Zach and Paul both have a rare genetic form of prion disease.My friend Charlie Clark began complaining that his eyeglasses were faulty in September 2023. A trip to the optician didn’t fix them; they were still “out of alignment,” he said. The same month, his insomnia, a decades-old problem, became a torment. Still, at age 70, Charlie, a dogged journalist and prominent local historian in Arlington, Virginia, was thriving.
Prion diseases are rare or ultrarare. There are between one and two new cases per 1 million people annually, mostly in people older than 60. In the United States, that comes to about 500 cases diagnosed each year, the vast majority of them CJD . Other animals have their prion diseases: scrapie in sheep and chronic wasting disease in deer and other cervids, which has been reported in 32 U.S states and five Canadian provinces.
In a story that is now widely told, Vallabh and Minikel, a transportation consultant, transformed their lives. They left their jobs and earned Ph.D.s in biomedical science at Harvard. They launched a shared lab at Broad. They began calling themselves “patient-scientists.” Minikel refers to prion disease as “our disease.”
Their slides laid out a case that removing normal prion protein wasn’t likely to be harmful. The healthy protein is anchored on the cell membranes of neurons and glia throughout the brain, although its best validated role is in maintaining myelination of peripheral nerves. It may also play roles in neural development, the establishment and proper functioning of synapses, and protecting neurons from cellular stress.
Meanwhile, propelled by Vallabh and Minikel’s successes and progress from its own internal research group, Ionis designed ASOs to treat people. When the ASO binds to the mRNA encoding normal prion protein, it summons an enzyme that destroys the mRNA. The ASO is then freed up to target another mRNA molecule. In 2021, the company selected a molecule for human testing, ION717, and soon won U.S Food and Drug Administration approval to move into clinical trials.
Paul, a big, bald man with a full gray mustache and beard, retired from his job in 2023. He says he’s enrolling in the trial “to help everybody,” but also in hopes it might touch his symptoms. “I’m all for it if it … my daily life just a little better,” he manages, through sobs. Emotional lability is a common symptom of prion disease. The ready tears are “a complete flip” from Paul’s predisease personality, notes his wife, Billi Hoffman.