Nutritional Genomics Uncovers Vitamin B3 Therapy as Curative for NAXD Disease

ABSTRACT: Vitamins are essential metabolites that must be obtained from external sources. All 13 vitamins were identified in the early 1900s, a rich era of biochemistry. More recently, they are consumed indiscriminately. We introduce a new nutritional genomics framework that begins with a treatment and identifies all potential disease candidates. Using a genome-wide CRISPR screen at varying vitamin B3 levels, we nominated dozens of diseases for B3-based therapy. The top candidate was NAXD, a proofreading enzyme involved in correcting an aberrant form of NADH (NADHX). Mutations in NAXD cause severe neurodevelopmental disease, with no proven therapies. We created a new mouse model of disease, observing NADHX accumulation and NAD+ depletion in affected organs, leading to impaired serine biosynthesis. Low B3 diets worsened the disease, while B3 supplementation was curative, extending lifespan by more than 20-fold. This work introduces a new approach to nutritional genomics and precision vitamin therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE304377 | GEO | 2026/02/06

REPOSITORIES: GEO