CRISPR Screening Advances Drug Target Discovery in Cancer and Neurodegenerative Diseases: From Preclinical Research to Clinical Translation — A Literature Review

Abstract

CRISPR/Cas9 technology enables genome-scale functional screening to identify genetic dependencies in cancer and neurodegenerative diseases (NDs) research. This review compares and contrasts how CRISPR screenings advance drug target discovery and clinical applications in both research fields. Literature search was conducted using PubMed, ScienceDirect, and Google Scholar, and keywords related to CRISPR, cancer, and NDs research. Reference lists were examined. Primary or review articles with full access, high relevance, and in English were selected, with 60 articles published between 2010 and 2026. In cancer research, the CRISPR knockout screen is the most common application of CRISPR technologies. It uses single guide RNA depletion or enrichment following the screen as readouts. This enables identification of genes essential for survival, part of synthetic lethal pathways, drug resistance mechanisms, and regulators of the tumor microenvironment. The Cancer Dependency Map is a large-scale platform that supports systematic identification of gene dependencies across diverse cancer cell lines. In NDs, CRISPR interference/activation (CRISPRi/a) screens are increasingly used in induced pluripotent stem cell (iPSC)-derived neurons or glia as they enable controllable partial gene repression or activation, without inducing DNA double-stranded breaks, and preserving post-mitotic neuronal functions. These screens can identify the toxic proteins, proteostasis/lysosomal pathways, oxidative stress, and neuron-glia interactions. CRISPRbrain is a large-scale platform that integrates gene function results from diverse human cell types. Clinically, translation is more common in cancer treatment, largely through ex vivo immune cell engineering, while clinical application for NDs remains limited. Multiple factors determine the optimal CRISPR approach, including biology of the given disease, readout type, and therapeutic goals. Both fields have intrinsic factors that lead to target identification biases. The clinical application of CRISPR faces barriers such as delivery, specificity, off-target effects, and immune responses, as well as additional challenges for CNS delivery in NDs. CRISPR screening is an essential strategy for target discovery in cancer and NDs research. The choice of the screening approach is highly context-dependent, particularly in terms of the underlying disease pathology and therapeutic goals. Future work should focus on developing more human-relevant models and improving the delivery system and gene engineering strategies to broaden clinical applications.