Novel Epigenetic Tool CHARM Offers Hope for Prion Disease Treatment

In a new study in mice, researchers introduce "CHARM," a compact and versatile epigenetic editor that can be used to silence prion protein throughout the brain. The tool provides a path towards an effective first-line treatment for patients with deadly prion disease as well as other neurodegenerative diseases caused by the toxic buildup of unwanted proteins.

Prion disease – a suite of devastating neurodegenerative disorders that result in rapid-onset dementia and death – is caused by misfolding of the prion protein, PrP, to form toxic aggregates that result in neuronal death. Previous research in mice has shown that removing PrP from neurons can halt prion disease and reverse symptoms, indicating that strategies aimed at reducing PrP expression may represent a viable therapeutic approach even after the onset of symptoms. However, long-term and reversible silencing of PrP-expressing genes using current approaches, such as CRISPRoff, remains a challenge, necessitating the development of a more compact, potent, and safe epigenetic tool. To address this need, Edwin Neumann and colleagues developed a compact and programmable epigenetic silencer called CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase), which is capable of silencing targeted genes with high specificity through programmable DNA methylation. The approach, which does not require DNA sequence edits, offers a potentially less cytotoxic alternative to genome-editing techniques that disrupt coding regions or splice sites. Neumann et al. show that CHARM platform can efficiently shut off the prion gene in most neurons throughout the entire mouse brain when delivered systemically by an adeno-associated virus (AAV) without altering the underlying DNA sequence.

According to the findings, the approach resulted in more than 80% brain-wide knockdown of PrP expression, greatly exceeding the currently recognized minimal knockdown required for therapeutic effects. Moreover, the authors demonstrate the ability to create self-silencing CHARM editors that turn themselves off after silencing target genes, thereby avoiding potential toxicity and other adverse effects from chronic expression in neurons.

"With the development of CHARMs, Neumann et al. have introduced a potent and safe editing technology for gene silencing via AAV delivery into otherwise difficult-to-target organs, such as the brain," write Madelynn Whittaker and Kiran Musunuru in a related Perspective.