Project Grant R01GM158880

The National Institute of General Medical Sciences awarded the University of Pittsburgh $414,677 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop novel peptide nucleic acid (PNA) approaches for targeting mitochondrial DNA heteroplasmy in primary mitochondrial diseases.

The funded research addresses the lack of approved methods to selectively modify or repair pathogenic mitochondrial DNA variants. The project integrates three complementary aims: defining the cellular and molecular mechanisms by which a novel mitochondrial delivery scaffold (CPM3) imports G-modified peptide nucleic acids into the mitochondrial matrix via endosomal trafficking; determining how these GPNAs remodel mitochondrial nucleoids, stall replication of mutant genomes, and promote selective degradation of variant mtDNA; and evaluating heteroplasmy shift, mitochondrial and contractile functional rescue, and cellular safety in patient-derived induced pluripotent stem cell cardiomyocytes. The work builds on preliminary demonstration that CPM3 achieves efficient and selective GPNA import into mitochondria, strand-invasive GPNA binding at the m.3243A>G pathogenic variant, and washout-dependent heteroplasmy shifts favoring wild-type genomes in both 143B cells and iPSC-derived cardiomyocytes.

Work is performed at the University of Pittsburgh, Pittsburgh, Pennsylvania. The period of performance runs from September 1, 2026, through August 31, 2030. This is a Project Grant, the standard NIH investigator-initiated research award mechanism.