{"entity":{"id":"idea-bio1-epigenetic-silencing-in-vivo","kind":"idea","name":"Switch off an undruggable oncogene permanently with epigenetic editing","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":[],"cancers":["neuroblastoma"],"sections":[],"technologies":["crispr-screens","epigenetic-drugs","methylation-profiling"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":9},"route":"/ideas/idea-bio1-epigenetic-silencing-in-vivo/","neighbours":{"cancer":[{"id":"neuroblastoma","kind":"cancer","name":"Neuroblastoma (paediatric)","route":"/cancers/neuroblastoma/"}],"technology":[{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"}]}}