Fig. 4: Treatment with Ksp-ABE9-dual-AAV9 particles delays cyst growth but has no effect on heart hypertrophy in Pkd1^RC/RC mice.

a Schematics of kidney specific promoter mediated dual AAV vectors (not to scale) that encode an amino-terminal fragment (N-term) and carboxyl-terminal fragment (C-term) that form base editors after protein splicing. b Representative histological images of kidneys from Pkd1^RC/RC mice injected with 1 × 10¹² vg of Ksp-ABE9-dual-AAV9 at PN14. Scale bar, 1 mm. c Percent cystic area relative to total kidney area of kidneys from Pkd1^RC/RC mice treated with 1 × 10¹² vg of Cbh-ABE9-dual-AAV9 and Ksp-ABE9-dual-AAV9 as well as vehicle at PN14 (n = 10 independent replicates). d–f Treatment with 1 × 10¹² vg of Cbh-ABE9-dual-AAV9 and Ksp-ABE9-dual-AAV9 at PN14 decreased KW/BW ratios (d), BUN (e), and serum creatinine levels (f) in three-month-old Pkd1^RC/RC mice. (n = 10, equal numbers of male and female mice, the colors represent female (pink) and male mice (blue)). g Representative hearts and histological images of hearts from three-month-old Pkd1^RC/RC mice injected with 1 × 10¹² vg of Ksp-ABE9-dual-AAV9 and Cbh-ABE9-dual-AAV9 at PN14. Scale bar, 1 mm. h Treatment with 1 × 10¹² vg of Ksp-ABE9-dual-AAV9 has no effect on HW/BW ratios in three-month-old Pkd1^RC/RC mice (n = 10). ns, not significant. i The comparison of the editing efficiency (%) of the targeted pathogenic variant R3277C in kidneys and hearts as analyzed with high-throughput sequencing of gDNA in these tissues from three-month-old Pkd1^RC/RC mice injected with 1 × 10¹² vg of Cbh-ABE9-dual-AAV9 and Ksp-ABE9-dual-AAV9 at PN14 (n = 3 independent replicates). j–l Western blot analysis of PC1 protein in three-month-old wide type and age-matched Pkd1^RC/RC and wide type kidney (j), livers (k), and heart (l) treated with 1 × 10¹² vg of Ksp-ABE9-dual-AAV9 or vehicle at PN14 (n = 3 independent replicates). Values and error bars reflect mean ± SD from indicated counts of independent experiments, ns: p > 0.05, *p  <  0.05, **p  <  0.01, ***p  <  0.001 and ****p  <  0.0001 or as indicated in the figure, using two-tailed t-test. Source data are provided as a Source Data file.