Lipid nanoparticle mRNA therapy improves survival and reduces serum branched-chain amino acids in mouse models of maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare, inherited, metabolic disorder characterized by dysfunction of the multi-subunit, mitochondrial enzyme complex branched-chain alpha-keto acid dehydrogenase (BCKDH). BCKDH catalyzes the oxidative decarboxylation of branched-chain amino acids (BCAAs). BCAAs and their neurotoxic alpha-keto intermediates can accumulate in the blood and tissues in the absence of functional BCKDH. We evaluated a lipid nanoparticle (LNP)-based treatment approach to address all possible genetic mutations that can cause MSUD (BCKDHA, BCKDHB, and DBT). In the intermediate MSUD mouse model, which harbors a mutation in the dihydrolipoamide branched-chain transacylase E2 (DBT) subunit of BCKDH, repeated administration of LNP-encapsulated mRNA therapy significantly extended survival and reduced serum leucine levels. We also evaluated our LNP approach in several models of classic MSUD, namely DBT knockout (KO) mice and the new BCKDHA KO and BCKDHB KO mice. The latter two were generated by CRISPR/Cas9 gene editing and contain the highly prevalent classic MSUD-causing mutations seen in the Mennonite and Costa Rican populations. Intravenous LNP-encapsulated mRNA administration extended survival and increased body weight in the DBT KO and BCKDHA KO models of classic MSUD but was not effective in BCKDHB KO mice. Our data provide a promising proof-of-concept that a universal, mutation-independent approach to treating MSUD is possible and viable.