Project Grant R01HD121570

Federal Grant Award Summary

The National Institute of Child Health and Human Development (NICHD) awarded The Medical College of Wisconsin, Inc. a $722,631 Project Grant on June 17, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to validate the causality of disputed mitochondrial variants associated with inborn errors of metabolism. The research addresses primary mitochondrial disease (PMD), a multi-systemic disorder caused by impaired mitochondrial function resulting from pathogenic variants in either nuclear genes or mitochondrial DNA (mtDNA). The project will deliver functional validation of 23 mtDNA variants of uncertain significance (VUS) that were previously classified as pathogenic but lack sufficient functional data, thereby enabling definitive PMD diagnoses and supporting therapeutic development efforts.

Under Aim 1, the awardee will produce human 143B cell line models for 20 VUS using advanced mtDNA base editing techniques, with minimal off-target effects. The research will deliver comprehensive functional assays and single-cell genomics analysis (including mtSCATAC-seq and scRNA-seq) to assess heteroplasmy, genomic changes, mitochondrial ATP production, and oxidative phosphorylation capacity. These research products will be generated leveraging the expertise of the ClinGen Mitochondrial Disease curation panel and will extend through February 28, 2031, advancing the interpretation framework established by the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) for mtDNA variant classification.