Treatment of metabolic disorders using genomic technologies: Lessons from methylmalonic acidemia

Abstract

Hereditary methylmalonic acidemia (MMA) caused by deficiency of the enzyme methylmalonyl-CoA mutase (MMUT) is a relatively common and severe organic acidemia. The recalcitrant nature of the condition to conventional dietary and medical management has led to the use of elective liver and combined liver-kidney transplantation in some patients. However, liver transplantation is intrinsically limited by organ availability, the risks of surgery, procedural and life-long management costs, transplant comorbidities, and a remaining underlying risk of complications related to MMA despite transplantation. Here, we review pre-clinical studies that present alternative approaches to solid organ transplantation as a treatment for MMUT MMA, including adeno-associated viral gene addition therapy, mRNA therapy, and genome editing, with and without nuclease enhancement.

New Therapeutic Approaches to Inherited Metabolic Pediatric Epilepsies

“…Liver transplantation is optional when conventional treatment fails. 26 In recent years, several preclinical genetic-based therapeutics for MMA have resulted in favorable outcomes, 27 and there are ongoing clinical trials investigating these approaches (ClinicalTrials. gov; NCT04581785, NCT04899310, and NCT05506254).…”

Notes from the 2022 Folate, Vitamin B12, and One-Carbon Metabolism Conference

“…He also described a new post-translational modification called methylmalonylation and its involvement in disease pathophysiology, including a universal therapy for MMA that uses an engineered SIRT5 [31]. This work is encouraging and opens avenue for new genomic therapies to treat MMA based on the replacement of MUT expression [30] and the targeting of aberrant PTMs [31].…”

“…MMA is characterized by the build-up of methylmalonic acid, a "toxic" metabolite that forms due to mutations in the B12 enzyme methylmalonyl-CoA mutase (MUT) or the enzymes involved in the transport and synthesis of adenosylcobalamin. Charles Venditti (National Institutes of Health, Bethesda, MD, USA) overviewed recent work that used modified mRNA, AAV gene therapy and genome editing to treat this disorder [30]. He also described a new post-translational modification called methylmalonylation and its involvement in disease pathophysiology, including a universal therapy for MMA that uses an engineered SIRT5 [31].…”

Gene therapy for organic acidemias: Lessons learned from methylmalonic and propionic acidemia

“…Preclinical gene therapy studies for OA have used mouse models made by a variety of strategies including knocking-out genes, transgenesis, and knocking-in orthologous patient mutations using genome editing (Table 1). 11,12 This has yielded mice with both severe, moderate and mild phenotypes. Here we review some of the murine models used in gene therapy experiments for MMA and PA.…”