This study was designed to specifically identify therapeutic compounds that can effectively prevent CCM lesion formation and progression through inhibition of the MEKK3-KLF-ADAMTS signaling axis. The strategy used an FDA-approved kinase screen to identify compounds that inhibited KLF2/4 gene expression levels in CCM1/2-deficient endothelial cells. Ponatinib was found to be the most promising candidate following in vitro studies and testing in in vivo mouse models of CCM lesion development. The endothelial-specific Ccm1 or Ccm2 knockout (Ccm1iECKO or Ccm2iECKO) mice on C57Bl/6 background were treated with sham or ponatinib. Animals were randomly assigned to treatment groups from litters with at least four pups. Only data from animal studies with the appropriate littermate controls (Cre-negative controls, Ccm1iECKO or Ccm2iECKO pups treated with sham, and Ccm1iECKO or Ccm2iECKO treated with ponatinib) were included in the analysis. Therapeutic potential of ponatinib was examined by micro-CT for reductions in lesion number, size, and volume. Changes in gene expression were measured by qPCR. Restoration of misaligned endothelial lining was observed by scanning electron microscopy.

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