Figure 6.
Oral rebastinib treatment prevents CCM formation but does not arrest CCM growth in the two-hit adult mouse model. (A) Schematic representation of adult Krit1fl/fl; iPik3caH1047R mice, aged 8–10 wk, underwent craniotomy and received focal AAV-Cre injections. Mice were randomly assigned to receive either rebastinib (10 mg/kg) or vehicle by oral gavage immediately after full recovery from anesthesia. Treatment was continued every 24 h until POD 21. Live-animal microscopic images were captured through the cranial window from POD 7 to POD 21 to observe lesion formation and growth. (B) Serial of microscopic images through the cranial windows showing CCM growth in either vehicle- or rebastinib-treated mouse brains from POD 1 to POD 21. (C–E) Representative visual images (left panels) and microCT renders (right panels), and microCT quantification of (D) CCM lesion volumes (E) and total brain volumes of adult brains harvested on POD 21. Vehicle, n = 9; rebastinib, n = 13. The same microCT renders are also shown in Fig. S5 A to provide a comprehensive overview of the effects of rebastinib treatment on lesion burden across the entire study cohort. (F) Schematic representation of adult Krit1fl/fl; iPik3caH1047R mice, aged 8–10 wk, undergoing craniotomy, followed by focal AAV-Cre injection. Mice with CCM lesion size between 0.5 and 1.0 mm on POD 11 were randomly assigned to receive either rebastinib (10 mg/kg) or vehicle by oral gavage. Treatment was continued every 24 h until POD 28. Live-animal microscopic images were captured through the cranial window from POD 11 to POD 28 to observe lesion formation and growth. (G) Serial of microscopic images through the cranial windows showing CCM growth in either vehicle- or rebastinib-treated mouse brains from POD 11 to POD 28. The same microscopic images are also shown in Fig. S5 F to provide a comprehensive overview of the effects of rebastinib treatment on lesion burden across the entire study cohort. (H–J) Representative visual images (left panels) and microCT renders (right panels), and microCT quantification of (I) CCM lesion volumes (J) and total brain volumes of adult brains harvested on POD 21. Scale bar: 1 mm. (K) Kaplan–Meier survival curves showing animal loss of the study. Vehicle, n = 8; rebastinib, n = 9. Data shown are means ± SEM. **P <0.0001 by two-tailed Mann–Whitney U test. No statistically significant (n.s.) differences are observed in (E) P = 0.6825, (K) P = 0.1208, (I) P = 0.1447, and (J) P = 0.0879. Refer to the image caption for details. Panel A shows a schematic of the experimental setup where adult K r i t 1 f l slash f l; i P i k 3 c a H 1047 R mice underwent craniotomy. Mice were treated with either Rebastinib or a vehicle. Panel B displays a series of microscopic images showing C C M growth in vehicle- or Rebastinib-treated mouse brains. Panel C presents representative visual images and micro C T renders of adult brains harvested on P O D 21, with quantification of C C M lesion volumes and total brain volumes shown in Panels D and E. Panel F shows a similar schematic for a different experimental setup where treatment started on P O D 11. Panel G displays a series of microscopic images showing C C M growth in vehicle- or Rebastinib-treated mouse brains. Panel H presents representative visual images and micro C T renders of adult brains harvested on P O D 28, with quantification of C C M lesion volumes and total brain volumes shown in Panels I and J. Panel K shows Kaplan-Meier survival curves indicating animal loss during the study.

Oral rebastinib treatment prevents CCM formation but does not arrest CCM growth in the two-hit adult mouse model. (A) Schematic representation of adult Krit1fl/fl; iPik3caH1047R mice, aged 8–10 wk, underwent craniotomy and received focal AAV-Cre injections. Mice were randomly assigned to receive either rebastinib (10 mg/kg) or vehicle by oral gavage immediately after full recovery from anesthesia. Treatment was continued every 24 h until POD 21. Live-animal microscopic images were captured through the cranial window from POD 7 to POD 21 to observe lesion formation and growth. (B) Serial of microscopic images through the cranial windows showing CCM growth in either vehicle- or rebastinib-treated mouse brains from POD 1 to POD 21. (C–E) Representative visual images (left panels) and microCT renders (right panels), and microCT quantification of (D) CCM lesion volumes (E) and total brain volumes of adult brains harvested on POD 21. Vehicle, n = 9; rebastinib, n = 13. The same microCT renders are also shown in Fig. S5 A to provide a comprehensive overview of the effects of rebastinib treatment on lesion burden across the entire study cohort. (F) Schematic representation of adult Krit1fl/fl; iPik3caH1047R mice, aged 8–10 wk, undergoing craniotomy, followed by focal AAV-Cre injection. Mice with CCM lesion size between 0.5 and 1.0 mm on POD 11 were randomly assigned to receive either rebastinib (10 mg/kg) or vehicle by oral gavage. Treatment was continued every 24 h until POD 28. Live-animal microscopic images were captured through the cranial window from POD 11 to POD 28 to observe lesion formation and growth. (G) Serial of microscopic images through the cranial windows showing CCM growth in either vehicle- or rebastinib-treated mouse brains from POD 11 to POD 28. The same microscopic images are also shown in Fig. S5 F to provide a comprehensive overview of the effects of rebastinib treatment on lesion burden across the entire study cohort. (H–J) Representative visual images (left panels) and microCT renders (right panels), and microCT quantification of (I) CCM lesion volumes (J) and total brain volumes of adult brains harvested on POD 21. Scale bar: 1 mm. (K) Kaplan–Meier survival curves showing animal loss of the study. Vehicle, n = 8; rebastinib, n = 9. Data shown are means ± SEM. **P <0.0001 by two-tailed Mann–Whitney U test. No statistically significant (n.s.) differences are observed in (E) P = 0.6825, (K) P = 0.1208, (I) P = 0.1447, and (J) P = 0.0879.

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