# Switch off an undruggable oncogene permanently with epigenetic editing

Source: https://onco.cc/ideas/idea-bio1-epigenetic-silencing-in-vivo/  
OnCo record `idea-bio1-epigenetic-silencing-in-vivo` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Instead of blocking a cancer protein, add a chemical off-switch to its gene so the cell stops making it. Early versions of this tool are being tested in other diseases.

## Summary

CRISPR-based epigenetic silencers (CRISPRoff and related systems) place heritable DNA methylation and repressive marks at a promoter without cutting DNA. Delivered by lipid nanoparticles, this could durably silence an amplified or overexpressed but undruggable oncogene. Epigenetic editing has entered clinical development for a liver target, establishing delivery and durability precedent in humans.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: A single LNP dose of an epigenetic silencer targeting an amplified oncogene achieves durable transcript suppression in tumour tissue for more than four weeks and inhibits tumour growth.
- Rationale: Silencing avoids the need for a binding pocket entirely, and heritable repression means dividing tumour cells retain the off state. Tumour-selective delivery remains the main risk.
- Proposed test: In a MYCN-amplified neuroblastoma model, compare tumour and liver transcript silencing and durability after systemic LNP dosing, with methylation sequencing to confirm mechanism and off-target promoter analysis.
- Maturity: speculative
- Actor: research

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- cancers: [Neuroblastoma (paediatric)](https://onco.cc/cancers/neuroblastoma/)
- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/)

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