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.