mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice

• DOI: 10.1161/strokeaha.123.044108
• Publication Date: 2023-09-25T09:00:46Z
• Authors: Lun Li; Aileen A. Ren; Siqi Gao; Yourong S. Su; Jisheng Yang; Jenna Bockman; Patricia Mericko-...; Joanna Griffin; Robert Shenkar; Roberto Alcazar; Thomas Moore; Rhonda Lightle; Dorothy DeBiasse; Issam A. Awad; Douglas A. Marchuk; Mark L. Kahn; Jan-Karl Burkhardt
• Keywords: Adult; Sirolimus; Mice; Hemangioma, Cavernous, Central Nervous System; Phosphatidylinositol 3-Kinases; Class I Phosphatidylinositol 3-Kinases; Animals; Humans; Endothelial Cells; 3. Good health

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular that frequently cause stroke. CCMs arise due to loss of function in one the genes encode CCM complex, a negative regulator MEKK3-KLF2/4 signaling endothelial cells. Gain-of-function mutations PIK3CA (encoding enzymatic subunit PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize gene loss-of-function generate rapidly growing lesions. METHODS: We recently developed model formation closely reproduces key events human through inducible and gain-of-function mature mice. In present study, we use this test ability rapamycin, clinically approved inhibitor effector mTORC1, treat CCMs. RESULTS: show both intraperitoneal oral administration rapamycin arrests growth, reduces perilesional iron deposition, improves perfusion within CONCLUSIONS: Our findings further establish adult as valuable preclinical support clinical testing