Novel Murine Models of Cerebral Cavernous Malformations

Jul 26, 2020Angiogenesis

New Mouse Models for Studying Brain Blood Vessel Malformations

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Abstract

Approximately 0.5% of the population develops cerebral cavernous malformations (CCMs), which can lead to serious neurological symptoms.

Patients with CCMs may experience headaches, seizures, and hemorrhages.
Current treatment options are limited to surgical removal of symptomatic CCMs, with no pharmaceutical therapies available.
Existing mouse models often induce severe CCMs early in life, limiting the timeframe for drug testing.
An inducible CCM3 mouse model was developed, allowing CCMs to form after weaning and extending the period for potential treatment.
Three proposed therapies—fasudil, tempol, and vitamin D—did not significantly reduce CCM formation when administered for 5 weeks.
New models enable focused studies on chronic and acute hemorrhage associated with CCMs, enhancing the potential for future drug development.

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Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D, and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for 5 weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage. 3

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Novel Murine Models of Cerebral Cavernous Malformations

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