BACKGROUND AND PURPOSE: Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal-dominant) forms with mutations in 1 of 3 gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase. Although Rho kinase inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo. METHODS: Our recently generated a model of CCM1 disease (Ccm1(+/-)Msh2(-/-)) was treated with the Rho kinase inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals' brains. For comparison, we also assessed therapeutic effect in previously described Ccm2(+/-)Trp53(-/-) mice treated with the same dose and duration of fasudil and placebo. RESULTS: Fasudil-treated Ccm1(+/-)Msh2(-/-) mice had a significantly decreased prevalence of CCM lesions compared with placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation, and endothelial proliferation and exhibited decreased expression of Rho kinase activation biomarkers. A therapeutic effect was also documented in Ccm2(+/-)Trp53(-/-) mice. CONCLUSIONS: This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs and indicates that Rho kinase activation is a critical step in CCM lesion genesis and maturation.
BACKGROUND AND PURPOSE:Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal-dominant) forms with mutations in 1 of 3 gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase. Although Rho kinase inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo. METHODS: Our recently generated a model of CCM1 disease (Ccm1(+/-)Msh2(-/-)) was treated with the Rho kinase inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals' brains. For comparison, we also assessed therapeutic effect in previously described Ccm2(+/-)Trp53(-/-) mice treated with the same dose and duration of fasudil and placebo. RESULTS:Fasudil-treated Ccm1(+/-)Msh2(-/-) mice had a significantly decreased prevalence of CCM lesions compared with placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation, and endothelial proliferation and exhibited decreased expression of Rho kinase activation biomarkers. A therapeutic effect was also documented in Ccm2(+/-)Trp53(-/-) mice. CONCLUSIONS: This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs and indicates that Rho kinase activation is a critical step in CCM lesion genesis and maturation.
Authors: T Sahoo; E W Johnson; J W Thomas; P M Kuehl; T L Jones; C G Dokken; J W Touchman; C J Gallione; S Q Lee-Lin; B Kosofsky; J H Kurth; D N Louis; G Mettler; L Morrison; A Gil-Nagel; S S Rich; J M Zabramski; M S Boguski; E D Green; D A Marchuk Journal: Hum Mol Genet Date: 1999-11 Impact factor: 6.150
Authors: S Laberge-le Couteulx; H H Jung; P Labauge; J P Houtteville; C Lescoat; M Cecillon; E Marechal; A Joutel; J F Bach; E Tournier-Lasserve Journal: Nat Genet Date: 1999-10 Impact factor: 38.330
Authors: Robert Shenkar; Palamadai N Venkatasubramanian; Alice M Wyrwicz; Jin-cheng Zhao; Changbin Shi; Amy Akers; Douglas A Marchuk; Issam A Awad Journal: Neurosurgery Date: 2008-10 Impact factor: 4.654
Authors: Amy L Akers; Eric Johnson; Gary K Steinberg; Joseph M Zabramski; Douglas A Marchuk Journal: Hum Mol Genet Date: 2008-12-16 Impact factor: 6.150
Authors: Kevin J Whitehead; Aubrey C Chan; Sutip Navankasattusas; Wonshill Koh; Nyall R London; Jing Ling; Anne H Mayo; Stavros G Drakos; Christopher A Jones; Weiquan Zhu; Douglas A Marchuk; George E Davis; Dean Y Li Journal: Nat Med Date: 2009-01-18 Impact factor: 53.440
Authors: Basem M William; Wei An; Dan Feng; Scott Nadeau; Bhopal C Mohapatra; Matthew A Storck; Vimla Band; Hamid Band Journal: Hematology Date: 2015-07-15 Impact factor: 2.269
Authors: Sayoko Nishimura; Ketu Mishra-Gorur; JinSeok Park; Yulia V Surovtseva; Said M Sebti; Andre Levchenko; Angeliki Louvi; Murat Gunel Journal: Proc Natl Acad Sci U S A Date: 2017-05-12 Impact factor: 11.205
Authors: Christopher C Gibson; Weiquan Zhu; Chadwick T Davis; Jay A Bowman-Kirigin; Aubrey C Chan; Jing Ling; Ashley E Walker; Luca Goitre; Simona Delle Monache; Saverio Francesco Retta; Yan-Ting E Shiu; Allie H Grossmann; Kirk R Thomas; Anthony J Donato; Lisa A Lesniewski; Kevin J Whitehead; Dean Y Li Journal: Circulation Date: 2014-12-08 Impact factor: 29.690