CRISPR-Cas13d-Mediated Targeting of a Context-Specific Essential Gene Enables Selective Elimination of Uveal Melanoma.

ABSTRACT: Uveal melanoma, the most common eye cancer in adults, remains limited to surgical intervention and chemotherapy, with a dismal survival rate that has not improved in over 50 years. To address this therapeutic impasse, we systematically analyzed public gene expression, RNAi, and CRISPR knockout datasets and identified RASGRP3 as an essential gene specifically for uveal melanoma. RasGRP3 is uniquely overexpressed and essential for survival in uveal melanoma cells, but dispensable in healthy cells. RasGRP3 remains "undruggable" due to its intracellular localization and lack of targetable binding pockets. To overcome this, we developed a CRISPR-Cas13d RNA-targeting therapeutic that specifically knocks down RasGRP3 mRNA. This Cas13d-based therapeutic mediates selective uveal melanoma killing th

SUBMITTER: Stauber D 

PROVIDER: S-EPMC12393512 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature