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Genetic Prioritization, Therapeutic Repositioning and Cross-Disease Comparisons Reveal Inflammatory Targets Tractable for Kidney Stone Disease

Background: Formation of kidney stones resulting in urological disorders remains a major cause of morbidity in renal diseases and many others. Innate immunity, mainly inflammasome, has demonstrated a key role in the development of kidney stone disease (or "nephrolithiasis"), but a molecular rationale for therapeutic intervention targeting immunity is far from clear. We reason that identifying inflammatory gene networks underlying disease risk would inform immunotherapeutic targets for candidate drug discovery.

Results: We generated an atlas of genetic target prioritization, with the top targets highly enriched for genes involved in the NF-kB regulation, including interaction neighbors of inflammasome genes. We identified a network of highly ranked and interconnecting genes that are of functional relevance to nephrolithiasis and mediate crosstalk between inflammatory pathways. Crosstalk genes can be utilized for therapeutic repositioning, as highlighted by identification of ulixertinib and losmapimod that are both under clinical investigation as inhibitors of inflammatory mediators. Finally, we performed cross-disease comparisons and druggable pocket predictions, identifying inflammatory targets that are specific to and tractable for nephrolithiasis.

Conclusion: Genetic targets and candidate drugs, in silico identified in this study, provide the rich information of how to target innate immune pathways, with the potential of advancing immunotherapeutic strategies for nephrolithiasis.

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S7854 Ulixertinib (BVD-523) Ulixertinib (BVD-523, VRT752271) is a potent and reversible ERK1/ERK2 inhibitor with IC50 of <0.3 nM for ERK2. Phase 1.

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