Figure 5. Repeat i.v. Administration of hMUT mRNA Improved Survival and Ameliorated Metabolic Alterations in mut⁰ MMA Mice.

To explore the dosage and dosing frequency, Mut^−/−;Tg^INS-MCK-Mut mice received a single i.v. injection of hMUT mRNA at 0.05–0.5 mg/kg (n = 6–7). Mice were bled 4 days before and 3, 7, 10, and 14 days after a single i.v. injection.

(A) Plasma methylmalonic acid response and duration of effect across 3 doses (0.05, 0.2, 0.5 mg/kg). Mut^−/−;Tg^INS-MCK-Mut mice received weekly i.v. injections of hMUT mRNA or a control mRNA for 5 doses at 0.2 mg/kg.

(B) Survival curve of untreated, control mRNA and hMUT mRNA-treated Mut^−/−;Tg^INS-MCK-Mut mice. **p < 0.01 from log-rank test.

(C) Plasma methylmalonic acid concentrations 3 days after each dose in Mut^−/−;Tg^INS-MCK-Mut mice. Plasma methylmalonic acid concentrations 6 days after each hMUT mRNA dose were similar to concentrations measured 3 days after each dose (data not presented). Arrows indicate the day of injection. WO = 10 day washout following the last i.v. injection.

(A–C) Data shown as median ± MAD (A) and mean ± SD (B and C). *p < 0.05, p values obtained from Tukey’s multiple-comparison test after one-way ANOVA.