AI-Guided Genome-Wide CRISPR Platform for Novel Skin Therapeutics

SUMMARY

AI-guided CRISPR platform enables precise identification of novel therapeutic targets in primary cells, significantly enhancing drug discovery efficiency and facilitating the development of topical treatments for inflammatory skin diseases such as psoriasis

The Unmet Need: Current drug discovery lacks effective methods for target identification in physiologically relevant primary cells

• Traditional genome-wide CRISPR screening in primary cells faces substantial technical challenges, including inefficient transduction and biases toward well-characterized genes within existing disease-gene databases, limiting the discovery of novel, druggable targets; furthermore, conventional statistical hit calling inadequately assesses target novelty or therapeutic potential.

• Advancements in AI and functional genomics, combined with the increasing importance of physiologically relevant cellular models, are driving a new paradigm in drug discovery that emphasizes high-throughput, data-driven identification of targets directly in primary human cells across various disease contexts.

The Proposed Solution: Integrated AI-augmented genome-wide CRISPR knockout screening platform identifies high-novelty therapeutic targets in primary cells through receptor-expression phenotyping and machine learning analysis

• The faculty inventor developed a platform combining spinoculation-based transduction of a genome-wide CRISPR library in primary human keratinocytes with fluorescence-activated cell sorting of cells by receptor expression, followed by sequencing and computational analysis using VirtualCRISPR, a large language model trained on functional-genomics data, to predict gene phenotype probabilities and prioritize novel targets.

• This approach overcomes limitations of traditional screening by integrating experimental and AI-predicted data to reveal unconventional regulators, validated in murine models and human organotypic skin cultures, with applicability across multiple primary cell types and disease indications involving inflammatory, oncologic, and epithelial biology.

ADVANTAGES

• Identification of novel, high-novelty therapeutic targets

• Direct screening in physiologically relevant primary cells

• Integration of AI-guided functional-genomics prediction

• Polymer-free optimized transduction method

• Demonstrated in vitro and in vivo validation

• Generalizable to diverse cell types and disease contexts

APPLICATIONS

• Topical treatment development for psoriasis and inflammatory skin diseases

• Identification of drug targets for atopic dermatitis and hidradenitis suppurativa

• Therapeutic target discovery in oncology and rare inflammatory disorders