WASHINGTON (dpa-AFX) - In an article published in the journal Science, titled 'Brain-wide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor', Sonia Vallabh, PhD, who is a senior group leader at the Broad Institute, teamed up with Jonathan Weissman, PhD, a core member at the Whitehead Institute, to develop a groundbreaking method for targeting prion diseases. These diseases are fatal neurodegenerative disorders caused by misfolded prion proteins in the brain.
The researchers introduced a compact enzyme-free epigenetic editor called CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase) to suppress the expression of prion proteins in the brain. This new approach addressed the previous challenges posed by the large genetic components of existing technologies, such as CRISPRoff, developed by the Weissman lab, which utilizes methyl group addition to silence specific genes. Delivering CRISPRoff to brain cells had proven difficult due to its size.
To overcome this obstacle, Weissman and his team devised CHARM, which uses zinc-finger proteins to guide gene targeting. These proteins are small enough to be delivered via an adeno-associated virus vector. CHARM was further refined to recruit and activate DNA methyltransferases within cells, reducing toxic effects linked to external molecules.
Weissman emphasized the effectiveness of CHARM in reducing PrP expression by over 80% throughout the entire brain in healthy mice, surpassing the therapeutic threshold. Notably, CHARM was engineered to self-deactivate after gene silencing to prevent unintended side effects. Preliminary findings suggest that the removal of these proteins should not have adverse effects in healthy adults, potentially halting symptom progression in affected individuals.
The researchers are now working on optimizing CHARM to enhance its efficacy, safety, and scalability for future clinical trials. CHARMs are currently undergoing therapeutic testing in mice and show promise in treating diseases characterized by abnormal protein accumulation, such as Parkinson's and Alzheimer's. However, despite these advancements, the transition from research to clinical application remains a complex and lengthy process, as CHARMs require further refinement before becoming a viable medical option for prion diseases and related conditions.
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