Gene and nucleic acid therapies for MMUT-deficient methylmalonic acidemia: from AAV-mediated gene addition to LNP-mediated mRNA delivery and precision genome editing
TL;DR
Current therapeutic evidence is concentrated primarily in MMUT- deficient isolated MMA, and further progress will require safer and more durable delivery platforms, improved tissue targeting, robust long-term safety assessment, clinically meaningful endpoints, and careful evaluation of accessibility and cost.
Abstract
Methylmalonic acidemia (MMA) comprises a heterogeneous group of inherited metabolic disorders characterized by the accumulation of methylmalonic acid and related toxic metabolites. Among these conditions, isolated MMA caused by pathogenic variants in MMUT is the disease subtype in which gene and nucleic acid therapies have been investigated most extensively. Current management, including dietary protein restriction, L-carnitine supplementation, acute decompensation management, assessment of cobalamin responsiveness, and liver or combined liver-kidney transplantation, can improve metabolic stability but often remains insufficient to prevent recurrent metabolic crises, neurological injury, renal impairment, and reduced quality of life. This review summarizes the development of gene and nucleic acid therapies for MMUT- deficient MMA over the past three decades. The field has evolved from cellular correction and early nonviral, adenoviral, retroviral, and lentiviral approaches to adeno-associated virus (AAV)-mediated MMUT gene addition, albumin ( ALB )-locus genome editing, lipid nanoparticle (LNP)-mediated MMUT mRNA delivery, central nervous system and extrahepatic targeting, antisense-based splicing correction, mitochondrial protein delivery, and emerging precision-editing strategies. AAV8, AAV9, AAV44.9, and nuclease-free ALB -locus editing studies have provided a substantial preclinical foundation, while mRNA-based therapy and liver-directed genome editing have begun to enter clinical translation. However, AAV immunotoxicity, pre-existing neutralizing antibodies, redosing barriers, dilution of episomal transgene expression in the growing pediatric liver, incomplete correction of extrahepatic tissues, delivery safety, treatment burden, and cost remain major obstacles. Current therapeutic evidence is concentrated primarily in MMUT- deficient isolated MMA. Further progress will require safer and more durable delivery platforms, improved tissue targeting, robust long-term safety assessment, clinically meaningful endpoints, and careful evaluation of accessibility and cost.
