While George Clooney or Cate Blanchett exude a degree of charm, a captivating new epigenetic advance may outdo them both! A new study now describes a compact epigenetic editor known as “CHARM” that engages the cell’s own DNA methylation machinery to stop a fatal neurodegenerative disease in its tracks.
A charismatic crew guided by Sonia M. Vallabh and Jonathan S. Weissman knew that removing the troublesome, misfolded prion protein from neurons protected against neurodegenerative disease progression. Therefore, they sought to develop an epigenetic editing technology that could turn off prion gene expression in the brain while being non-toxic and small enough to fit into the viral vector required for systemic delivery. The cunningly designed and rather affable epigenetic editor – “Coupled Histone tail for Autoinhibition Release of Methyltransferase” or CHARM – represents a clinically translatable means of “pausing” prion disease progression without the need for ongoing mRNA/protein expression.
Let’s hear from Neumann, Bertozzi, and Colleagues on how the CHARM effector safely and effectively pauses prion disease:
- Direct fusion of a histone H3 tail to a non-catalytic Dnmt3l domain allows CHARM to recruit and activate endogenous DNA methyltransferases to methylate and silence the prion protein gene, which reduces transgene size and cytotoxicity
- CHARM acts independently of KRAB transcriptional repression domains and displays compatibility with DNA-binding tech such as dCas9, transcription activator-like effectors, and zinc finger proteins
- The small size of zinc finger proteins accommodates up to three DNA targeting elements (supporting multiplexing) or regulatory elements (conferring cell-type specificity) in a single adeno-associated virus (AAV) as part of the CHARM-associated epigenetic silencing platform
- Systemic delivery to the mouse brain prompts stable prion gene methylation and up to >80% brain-wide knockdown in prion protein levels in post-mitotic neurons (exceeding the minimal reduction required for therapeutic benefit) while displaying a lack of toxicity
- A previous study revealed that a 50% knockdown by an antisense oligonucleotide extended survival with five different prion strains, and as little as 21% knockdown delayed symptom onset
- Kinetically tuned self-silencing CHARMs autonomously deactivate after prion gene silencing, thereby temporally limiting CHARM expression to avoid antigenicity and any off-target activity from chronic expression
This delightful study highlights the potential of the CHARM effector in the development of a safe, compact, programmable, and deliverable epigenetic silencing platform that beguiles the epigenetic machinations of cells and may represent a viable therapy for prion disease or any number of neurodegenerative diseases induced by unwanted protein accumulation.
“From the perspectives of both toxicity and size, it made sense to recruit the machinery that the cell already has; it was a much simpler, more elegant solution,” Co-first author Neumann stated. “Cells are already using methyltransferases all of the time, and we’re essentially just tricking them into turning off a gene that they would normally leave turned on.”
For more on how the CHARM effector enchants the endogenous DNA methylation machinery to pause prion disease progression, see Science, June 2024.