Vitamin B2 and B3 nutrigenomics reveals a therapy for NAXD disease.

Publication Year:

2026

Authors:

Ankur Garg, Skyler Y Blume, Helen Huynh, Alec M Barrios, Onurkan O Karabulut, Qian Zhao, Ayush D Midha, Adam W Turner, B Vittorio Resnick, Xuewen Chen, Ayushi Agrawal, JaeYeon Kim, Liuji Chen, Qitao Ran, Alison M Ryan, Reece C Larson, Mina Negahban, Sophia C K Nelson, Andrew C Yang, Michela Traglia, Reuben Thomas, Ramon Sun, Mercedes Paredes, M Ryan Corces, Hening Lin, Isha H Jain

PubMed ID:

41747729

Funding Grants:

CIRM Bridges to Stem Cell Research and Therapy

Public Summary:

Vitamins are essential metabolites that must be obtained from external sources and are widely available in today’s marketplace and pharmacies. Scientists at the Gladstone Institutes have developed a nutritional genomics framework to systematically identify diseases responsive to micronutrient modulation. Using the advanced technology of Genome-wide CRISPR screens, and varying the levels of vitamin B2 and B3, they were able to detect dozens of candidate disease genes amenable to rescue by individual vitamins. For example, their research indicates that low-vitamin B3 diets accelerated pathology, whereas vitamin B3 supplementation extended lifespan by more than 40-fold. Their findings establish a nutritional genomics framework and demonstrate the therapeutic potential of precision vitamin interventions.

Scientific Abstract:

Vitamins are essential metabolites that must be obtained from external sources. In modern times, they have become widely available, leading to their ad hoc consumption. We developed a nutritional genomics framework to systematically identify monogenic diseases responsive to micronutrient modulation. Genome-wide CRISPR screens under varying vitamin B2 and B3 levels revealed dozens of candidate disease genes amenable to rescue by individual vitamins. In the vitamin B3 screen, NAD(P)HX dehydratase (NAXD) was the top hit; this enzyme repairs an aberrant, hydrated form of NADH (6-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide [NADHX]), and its loss causes severe neurodevelopmental disease. In our Naxd knockout (KO) mouse, we observed NADHX accumulation, NAD(+) depletion, and impaired serine biosynthesis in neonatal KO brains. Spatial metabolomics, single-nuclei RNA sequencing (snRNA-seq), and histology pinpointed cortical and brain endothelial cell vulnerability. Low-vitamin B3 diets accelerated pathology, whereas vitamin B3 supplementation extended lifespan by more than 40-fold. These findings establish a nutritional genomics framework and demonstrate the therapeutic potential of precision vitamin interventions.