ND4 mRNA-LNP-mediated mitochondrial gene therapy for Leber hereditary optic neuropathy

초록

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder primarily caused by pathogenic mutations in mitochondrial DNA (mtDNA), most commonly the ND4 m.11778G>A mutation. These mutations impair mitochondrial respiration and lead to progressive retinal ganglion cell (RGC) degeneration and vision loss. Novel therapeutic approaches are needed to restore mitochondrial function and prevent retinal degeneration in patients with LHON. Our aim was to determine whether lipid nanoparticle (LNP)-mediated delivery of wild-type ND4 mRNA could restore mitochondrial function and improve retinal pathology in cellular and mouse models of LHON. To address this aim, ND4 mRNA was encapsulated in LNPs and administered to LHON mouse embryonic fibroblasts (MEFs) in vitro and to ND4 mutant mice by intravitreal injection in vivo. We found that ND4 mRNA-LNP treatment improved mitochondrial respiratory function and ATP production in LHON MEFs, indicating improved mitochondrial function. In vivo, ND4 mRNA-LNP–treated mice exhibited increased total retinal thickness, increased ganglion cell layer (GCL) thickness, and increased Brn3a-positive RGCs compared with Ctrl mRNA-LNP–treated mice. These findings suggest that ND4 mRNA-LNP treatment preserves retinal structure and protects against RGC loss in ND4 mutant mice. Collectively, these results demonstrate that ND4 mRNA-LNP delivery restores mitochondrial function and attenuates retinal degeneration in LHON models. These findings support the feasibility of mRNA-LNP–mediated mitochondrial gene replacement as a therapeutic strategy for LHON.