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Event Detail (Archived)

Brain-wide Silencing of Prion Protein and Treatment of Prion Diseases by AAV-Mediated Delivery of CHARM an Engineered Compact Epigenetic Editor 

The Jerry A. Weisbach Memorial Lecture

  • This event already took place in May 2024
  • Caspary Auditorium

Event Details

Friday Lecture Series
Jonathan Weissman, Ph.D., professor of biology, member, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; member and Landon T. Clay Professor of Biology, Whitehead Institute for Biomedical Research; investigator, Howard Hughes Medical Institute
Speaker bio(s)

Prion diseases are caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid-onset dementia and death. However, elimination of endogenous PrP halts prion disease progression. Here, we describe Coupled Histone tail for Autoinhibition Release of Methyltransferase (CHARM), a compact, enzyme-free epigenetic editor capable of silencing transcription through programmable DNA methylation. Using a histone H3 tail-Dnmt3l fusion, CHARM recruits and activates endogenous DNA methyltransferases, thereby reducing transgene size and cytotoxicity. When delivered to the mouse brain by a single injection of adeno-associated virus (AAV), Prnp-targeted CHARM ablates PrP expression across the brain and rescue prion infected mice even when administered after the onset of symptoms. Furthermore, we temporally limit editor expression by implementing a kinetically-tuned self- silencing approach. CHARM represents a broadly applicable strategy to suppress pathogenic proteins, including those implicated in other neurodegenerative diseases.

Jonathan Weissman, Ph.D., studies how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. He is also widely recognized for building innovative tools for broadly exploring organizational principles of biological systems. These include ribosome profiling, which globally monitors protein translation, CRISPRi/a for controlling the expression of human genes and rewiring the epigenome, and lineage tracing tools, to record the history of cells.

Dr. Weissman is a member of the National Academy of Sciences, a member of the Ludwig Center for Molecular Oncology, and a member of the European Molecular Biology Organization. Dr. Weissman also serves as a member on several Scientific Advisory Boards including Amgen, the Klarman Cell Observatory at Broad Institute, the Helen Hay Whitney Foundation, Stowers Institute for Biomedical Research, Tenaya Therapeutics, Tessera Therapeutics, and the Laboratory for Genomics Research. Additionally, he is the Head of SAB for the Innovative Genomics Institute.

Dr. Weissman has received numerous awards including the Beverly and Raymond Sackler International Prize in Biophysics (2008), The Keith Porter Award Lecture from the American Society of Cell Biology (2015), the National Academy Science Award for Scientific Discovery (2015), and the Ira Herskowitz Award from the Genetic Society of America (2020).

FLS lectures will take place in Caspary Auditorium and virtually via Zoom. We recommend virtual participants log out of VPN prior to logging in to Zoom. Please do not share the link or post on social media. This talk will not be recorded.

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