FIG. 4.
Increase in methylmalonyl-CoA mutase activity in mice treated with 2 × 1011 GC of AAV8-TBG-mMut. (A) Plasma methylmalonic acid (MMA) levels at 24, 60, 90, 120, 180, 270, and 360 days of life in untreated Mut–/– mice and Mut–/– mice treated with 2 × 1011 GC of rAAV8-TBG-mMut. The mean plasma MMA levels of untreated Mut–/– mice were 1,361 μM at 24 days (n = 13) and 1,120 μM at 60 days (n = 6). The mean plasma MMA levels of treated Mut–/– mice were considerably lower at 703 μM in mice 24 days old (n = 12; *p < 0.01) and 528 μM in mice 60 days old (n = 11; *p < 0.01). Plasma MMA levels in older mice stabilized between 345 and 465 μM after 90 days (n = 4–8 at each point). The plasma MMA levels in unaffected Mut+/− mice ranged from 5 to 10 μM. (B) In vivo [1-13C]propionate oxidation in Mut–/– mice 1 year after treatment with 2 × 1011 GC of rAAV8-TBG-mMut or 2 × 1011 GC of rAAV8-CBA-mMut. Mice were injected with 200 mg of sodium [1-13C]propionate and the percentage of dose oxidized was measured at 25 min. rAAV8-TBG-mMut-treated Mut–/– mice (n = 4) oxidized 32.5 ± 8.1% of the injected tracer, compared with 12.6 ± 2.2% by untreated Mut–/– mice (n = 9) (*p < 0.01). rAAV8-CBA-mMut-treated Mut–/– mice (n = 4) oxidized 39.8 ± 9.4% of the injected tracer (p value not significant vs. rAAV8-TBG-mMut-treated mice). Untreated Mut+/− mice (n = 12) oxidized 69.4 ± 4.3% of the injected tracer at the same time point. Error bars surround the 95% confidence intervals.