The Generative Brain

CHARM epigenetic editor (zinc finger guided DNA methylation)

CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase) is a compact epigenetic editor that uses a zinc finger protein to recruit the cell's own DNMT3A and methylate the PRNP promoter, silencing the gene without changing the DNA sequence. One IV injection of AAV lowered brain PrP by more than 80 percent in mice. Mouse-only.

Key facts

  • Published in Science on 28 June 2024 (Neumann, Bertozzi and colleagues; senior authors Jonathan Weissman and Sonia Vallabh, with Ben Deverman and Eric Minikel).
  • Design: a small zinc finger protein replaces Cas9 so the tool fits in an AAV; it recruits endogenous DNMT3A by attaching sections of DNMT3A partner molecules, so no outside enzyme is delivered.
  • A single intravenous AAV injection silenced the prion protein gene across the mouse brain and eliminated more than 80 percent of PrP (up to 80 percent after six weeks in the NIH summary).
  • The team engineered CHARM to switch itself off after silencing the gene, to reduce the chance of side effects.
  • CHARM works independently of KRAB repression domains, is compatible with dCas9, TALE and zinc finger binders, and a single AAV can carry up to three targeting or regulatory elements.
  • Press accounts cite earlier work showing that as little as 21 percent PrP reduction can improve symptoms, against more than 80 percent here.
  • Brain-wide delivery depends on an engineered AAV capsid from the Deverman lab (Science, 17 May 2024), described as bringing CHARM closer to clinical trials.

Timeline

  1. 2024Deverman lab brain-wide AAV vector published in Science.
  2. 2024Science paper published.
  3. 2024NIH Research Matters summary.
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