A Patient-Scientist Lens on How and Why to Move Faster to First in Human

Wednesday, December 3, 2025 | 2:00 to 3:00 p.m. ET

Sonia Vallabh, Ph.D.

Director, Prion Therapeutic Science

Broad Institute

svallabh@broadinstitute.org

Website

Sonia Vallabh co-leads the initiative to develop preventive drugs for prion disease at the Broad Institute of MIT and Harvard. She comes to this work with a personal mission. In 2010, Vallabh watched her 52-year-old mother die of a rapid, mysterious, undiagnosed dementia. One year later, Vallabh learned that her mother’s disease had been genetic prion disease, and that she herself was at risk. Vallabh underwent predictive genetic testing and learned that she had inherited the causal mutation, placing her at very high risk of developing the same disease. There was no prevention, treatment, or cure available. Vallabh quit her previous career in law and consulting, and, together with her husband, Eric Minikel, re-trained as a scientist in order to devote her life to finding a way to stop her disease before it starts.

At the Broad, Vallabh is focused on developing preventive drugs for prion disease. Lowering of prion protein (PrP) is a genetically well-validated strategy for delaying the onset of prion disease, and it lends itself to measurement of PrP as a biomarker available before the disease process has begun. Vallabh is working on the discovery and preclinical development of PrP-lowering drugs, including editing, epi-editing, and oligonucleotide strategies; credentialing of PrP in cerebrospinal fluid as a pharmacodynamic biomarker for such drugs; and establishment of a clinical pathway for preventive drug development. She co-leads a natural history study at Massachusetts General Hospital devoted to the assessment of fluid biomarkers in individuals at risk for genetic prion disease, and helped to launch the Prion Registry to promote and enable research participation in her community.

Vallabh holds a B.A. from Swarthmore College, a J.D. from Harvard Law School, and a Ph.D. in biological and biomedical sciences from Harvard University. She trained in Stuart Schreiber’s laboratory at the Broad. Her story has been told in The New Yorker, NPR, and WIRED.

Summary

Prion disease is a rapidly progressive neurodegenerative disease that is universally fatal and currently untreatable. It is caused by the gain of function of a single causal protein, the prion protein, which misfolds into a so-called "prion" which spreads its corrupted conformation across the brain. Many lines of evidence suggest that reducing PrP levels in the brain is an effective and safe strategy for treating and preventing prion disease, and multiple therapeutic platforms now offer promise for targeting one disease-causing protein in the CNS.

This talk will describe our lab's efforts to advance to small academic-initiated first-in-human studies both a divalent siRNA therapy for prion disease, and a one-time epigenetic therapy called CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase). Both di-siRNA and CHARM have been shown capable of dramatic disease modification in prion-infected mice. This talk will discuss the timelines and central challenges of these two rapidly advancing programs. Topics will include the pros and cons of oligo versus gene therapy for prion disease; regulatory feedback received for both programs; and the central clinical challenge in this rapidly progressive dementia – treating preventively. We will share our work, shaped by FDA input, across the domains of biomarker development, natural history and preclinical studies to enable preventive trials in healthy individuals with known high-penetrance PRNP variants. We will further describe how the mandate to extend healthy life, rather than just illness – one that is shared broadly across the field of neurodegeneration – guides our plans and mission.

This talk will be delivered from a patient-scientist perspective as Sonia Vallabh is both a prion disease researcher and herself a carrier of a high-penetrance pathogenic PRNP variant causal for genetic prion disease.

Learning Objectives:

1. Articulate the evidence for the safety and efficacy of prion protein lowering as a therapeutic strategy in prion disease.
2. Describe the distinct clinical challenges and opportunities posed by our two patient populations: symptomatic prion disease patients, and asymptomatic carriers of high penetrance pathogenic variants in the prion protein gene.