Fig. 3. Two doses of dual-AAV9 ABE8e increase atrial but not ventricular base editing.
a, Longitudinal echocardiographic measurements (defined in Fig. 2) of the LVPW (left panel), LVPW/LVDd ratio (middle panel) and %FS (right panel) in WT 129SvEv/S4 (n = 5 males, black line), untreated R403Q-129SvEv/S4 (n = 6 males, red line) and R403Q-129SvEv/S4 mice treated with two doses of dual-AAV9 ABE8e (n = 6 males, blue line). Untreated but not treated R403Q-129SvEv/S4 developed early-onset hypertrophy (increased LVPW thickness and increased LVPW/LVDd) and hypercontractility (increased FS). b, Left: representative Masson-trichrome-stained LV and RV histological sections from WT 129SvEv/S4 male (left), treated (two doses of AAV9 ABE8e) male R403Q-129SvEv/S4 (middle) and untreated R403Q-129SvEv/S4 (right) male mice. Collagen deposition (blue staining) within regions of myocardial fibrosis was prominent in the untreated but minimal in the treated mouse and WT mice. (Scale bar, 1 mm). Right panel: quantification of fibrosis from Masson-trichrome-stained ventricular sections (five per mouse) from untreated (n = 5 males) and treated (n = 3 males; two doses) of AAV9 ABE8e R403Q-129SvEv/S4 mice. c, Editing efficiency of the targeted R403Q allele and indels was assessed in LV gDNA derived from five treated and five untreated male mice. d, Editing efficiency was assessed by sequencing Myh6 cDNA derived from RNAs extracted from the LVs, RVs, LAs and RAs from three male mice. Atrial editing was increased after two doses. e, The mean percent of bystander edits was detected in pooled LV cDNAs from R403Q-129SvEv/S4 mice (n = 3 males) treated with two doses. Data are presented as mean values ± s.d., and significance was assessed by two-tailed t-test (Supplementary Information).