NOVEL THERAPEUTIC INTERVENTIONS FOR CEREBRAL CAVERNOUS MALFORMATIONS

The aim of the research

Main researcher ELISABETTA DEJANA

Cerebral Cavernous Malformation (CCM) is a rare genetic disorder characterized by malformations of blood vessels mostly localized in the brain.

These malformations are fragile and prone to leak causing a variety of neurological symptoms that severely affect life quality and survival of the patients. For example, CCM is the most frequent cause of hemorrhagic stroke in childhood. No pharmacological therapy is available at present and surgery is often not applicable due to the location of the malformations in un-accessible regions of the brain. Loss of function mutations in any one of three distinct genes, CCM1, CCM2 and CCM3 cause the pathology. The cell type mostly affected by such mutations is the endothelium that forms the internal cover of cerebral blood vessels and faces blood. In previous work we found that endothelial cells lining the CCM cavernomas present abnormal functional responses and that inhibitors of these responses can significantly reduce the malformations. In this project we plan to confirm and extend these observations. We will test a relatively large number of pharmacological inhibitors acting with different mechanism of action. The potential outcome of this project is the identification of one or more compounds to be tested in clinical trials on CCM patients. The goal of finding a cure to a rare genetic disease is relevant to Telethon's mission.

Scientific publications

2016 EMBO MOLECULAR MEDICINE
KLF4 is a key determinant in the development and progression of cerebral cavernous malformations
Cuttano, R; Rudini, N; Bravi, L; Corada, M; Giampietro, C; Papa, E; Morini, MF; Maddaluno, L; Baeyens, N; Adams, RH; Jain, MK; Owens, GK; Schwartz, M; Lampugnani, MG; Dejana, ECites: 1 (*)
2015 NATURE COMMUNICATIONS
PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence
Bonfanti, C; Rossi, G; Tedesco, FS; Giannotta, M; Benedetti, S; Tonlorenzi, R; Antonini, S; Marazzi, G; Dejana, E; Sassoon, D; Cossu, G; Messina, GCites: 7 (*)
2015 EMBO MOLECULAR MEDICINE
Defective autophagy is a key feature of cerebral cavernous malformations
Marchi, S; Corricelli, M; Trapani, E; Bravi, L; Pittaro, A; Delle Monache, S; Ferroni, L; Patergnani, S; Missiroli, S; Goitre, L; Trabalzini, L; Rimessi, A; Giorgi, C; Zavan, B; Cassoni, P; Dejana, E; Retta, SF; Pinton, PCites: 3 (*)
2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice
Bravi, L; Rudini, N; Cuttano, R; Giampietro, C; Maddaluno, L; Ferrarini, L; Adams, RH; Corada, M; Boulday, G; Tournier-Lasserve, E; Dejana, E; Lampugnani, MGCites: 7 (*)
2015 NATURE COMMUNICATIONS
The alternative splicing factor Nova2 regulates vascular development and lumen formation
Giampietro, C; Deflorian, G; Gallo, S; Di Matteo, A; Pradella, D; Bonomi, S; Belloni, E; Nyqvist, D; Quaranta, V; Confalonieri, S; Bertalot, G; Orsenigo, F; Pisati, F; Ferrero, E; Biamonti, G; Fredrickx, E; Taveggia, C; Wyatt, CDR; Irimia, M; Di Fiore, PPCites: 1 (*)
2014 ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Signaling Pathways in the Specification of Arteries and Veins