FIG. 1.

AAV‐Alb‐2A‐MMUT therapy improves the phenotype of MMA mice in a pilot study. (A) Schematic of AAV‐Alb‐2A‐MMUT vector integration and expression. Homologous recombination allows for site‐specific gene addition of human codon‐optimized MMUT into the mouse Alb locus upstream of the stop codon. This generates a fused allele under the control of the native Alb promoter producing a fused mRNA. The 2A peptide mediates ribosomal skipping, which generates two separate, functional proteins; Alb‐2A and MMUT. (B) Survival curve of Mmut^−/− mice treated (n = 4) with 8.6e¹¹ VG of AAVDJ‐Alb‐2A‐MMUT versus untreated Mmut^−/− mice (n = 7; *P < 0.02; log‐rank [Mantel‐Cox] test). (C) Plasma methylmalonic acid levels of neonatal lethal Mmut^−/− mice (n = 3, 3, 2, 2, and 2) were not significantly reduced compared to untreated historical Mmut^−/− animals (n = 13, 6, 0, 0, and 0). (D) Plasma methylmalonic acid levels in treated Mmut^–/–;Tg^{INS‐MCK‐Mmut} mice (n = 9, 6, and 3) treated with 8.6e¹¹‐2.5e¹² VG of AAV8‐Alb‐2A‐MMUT were significantly lower than untreated Mmut^–/–;Tg^{INS‐MCK‐Mmut} mice (n = 13, 13, and 4; *P < 0.05, ±). Error bars are ± the SEM.