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24.08.2019 | Original Article

A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease

verfasst von: Lisa McKerracher, Robert Shenkar, Matthew Abbinanti, Ying Cao, Amy Peiper, James K. Liao, Rhonda Lightle, Thomas Moore, Nicholas Hobson, Carol Gallione, Joerg Ruschel, Janne Koskimäki, Romuald Girard, Kenneth Rosen, Douglas A. Marchuk, Issam A. Awad

Erschienen in: Translational Stroke Research | Ausgabe 3/2020

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Abstract

Cavernous angioma (CA) is a vascular pathology caused by loss of function in one of the 3 CA genes (CCM1, CCM2, and CCM3) that result in rho kinase (ROCK) activation. We investigated a novel ROCK2 selective inhibitor for the ability to reduce brain lesion formation, growth, and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1^+/− and Ccm3^+/− mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1^+/− and Ccm3^+/− transgenic mice were treated for 3 (Ccm3^+/−) or 4 months (Ccm1^+/−), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion volumes were assessed by micro-computed tomography. BA-1049 reduced activation of ROCK2 in Ccm3^+/−Trp53^−/− lesions. Ccm1^+/−Msh2^−/− (n=68) and Ccm3^+/−Trp53^−/− (n=71) mice treated with BA-1049 or placebo showed a significant dose-dependent reduction in lesion volume after treatment with BA-1049, and a reduction in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for the treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.

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Titel: A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease
verfasst von: Lisa McKerracher
Robert Shenkar
Matthew Abbinanti
Ying Cao
Amy Peiper
James K. Liao
Rhonda Lightle
Thomas Moore
Nicholas Hobson
Carol Gallione
Joerg Ruschel
Janne Koskimäki
Romuald Girard
Kenneth Rosen
Douglas A. Marchuk
Issam A. Awad
Publikationsdatum: 24.08.2019
Verlag: Springer US
Erschienen in: Translational Stroke Research / Ausgabe 3/2020
Print ISSN: 1868-4483
Elektronische ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-019-00725-8

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