Novel diagnostic and therapeutic perspectives for CCM disease prevention and treatment
Domenica 23 Novembre 2014 19:09

An international cooperation between researchers of the University of Utah (Salt Lake City, UT, USA), coordinated by prof. Dean Li, and two research units of the CCM_Italia multidisciplinary research network (Torino and L’Aquila), coordinated by prof. Francesco Retta, has led to the demonstration that compounds endowed with antioxidant properties, including cholecalciferol (Vitamin D3) and tempol (a scavenger of superoxide), are effective in rescuing major phenotypes associated with loss-of-function of CCM genes in both human endothelial cells and a mouse model of CCM disease, suggesting that these two known drugs might be repurposed to treat CCM disease.

The relative paper is currently in press and will be soon available online. Further work is ongoing to determine whether the reported findings will translate to humans with CCM disease.

Notably, while supporting and strengthening the original discovery that oxidative stress may play a critical role in CCM disease (Goitre et al., 2010Goitre et al., 2012; Guazzi et al., 2012Goitre et al., 2014), leading to concrete therapeutic perspectives, the novel findings strongly support immediate amendment of research protocols on human patients with CCM to include measurements of both Vitamin D3 [25(OH)D3] and relevant biomarkers of oxidative stress. Indeed, whereas low levels of Vitamin D3 might constitute a potential risk factor for CCM disease progression and severity, blood tests for measuring levels of Vitamin D3 and biomarkers of oxidative stress may have diagnostic and prognostic value for the early assessment of high-risk groups of patients with CCM disease, thus facilitating clinical decision-making and prompt initiation of adequate therapy. Consistently, there is some evidence suggesting that CCM-related symptoms increase during the winter months, which would be consistent with seasonal variation in Vitamin D or the increased oxidative stress associated with inflammation due to typical winter infections such as influenza. On the other hand, the accessibility of Vitamin D3, which is inexpensive and widely available in supplement form, freely available outdoors to those with exposed skin, and has a wide safety margin, and the various clinical trials underway in the United States for tempol in a variety of conditions suggest that one or both of these drugs could be rapidly applied to the treatment of CCM disease.


What is CCM disease?

Cerebral Cavernous Malformations (CCM; OMIM 116860) (also known as cavernous angioma or cavernoma) are major vascular malformations having a raspberry-like appearance and consisting of closely clustered, abnormally dilated and leaky capillary channels (caverns) lined by a thin endothelium layer devoid of normal vessel structural components (Rigamonti 2011).

CCM disease has been recognized as a common clinical entity, having a prevalence of 0.3%-0.5% in the general population, and accounting for approximately 24 million people worldwide with a major impact on quality of life. It can occur as single or multiple lesions (even hundreds) ranging in size from a few millimeters to a few centimeters and, depending on the size and location, can be clinically silent or give rise to serious clinical symptoms such as headaches, neurological deficits, seizures, stroke, and intracerebral hemorrhage that can result in death.

Symptomatic disease typically begins in the third through fifth decades of life, although lesions have been described in all age groups, including young children, with no sex predominance. Diagnosis is commonly made by routine magnetic resonance imaging (MRI) screening, although detection is far more likely via gradient-echo (GRE) or susceptibility-weighted imaging (SWI), which can unmask small lesions. Generally, approximately 30% of people with CCM lesions eventually will develop clinical symptoms.


CCM disease in Italy

Symptomatic CCM disease is estimated to hit a number of Italian people ranging from 15,000 to 80,000. Specifically, it has been estimated that the sporadic (sCCM) and familial (fCCM) forms of CCM disease affect a number of Italian people ranging from 10,500 to 56,000 (2-9 cases per 10,000 inhabitants) and from 4,500 to 24,000 (0.75-4 cases per 10,000 inhabitants), respectively.

Despite CCM disease goes up to the Italian breaking news and headlines when it hits famous people, including recently the football player of the Roma soccer team Leandro Castan, its knowledge and risk awareness is generally poor within the society and very low even among medical doctors. Furthermore, while medications are available to treat some clinical symptoms caused by CCM lesions, including seizures and headaches, to date there are no direct therapeutic approaches for CCM disease, besides surgical removal of accessible lesions in patients with recurrent hemorrhage or intractable seizures. In particular, novel pharmacological strategies are required for preventing CCM disease progression and severity in susceptible individuals.

Italian researchers from the CCM Italia network have provided original and fundamental insights into the understanding of molecular mechanisms underlying CCM pathogenesis and the definition of novel pharmacological approaches for CCM disease prevention and treatment, including the recent important findings described above. However, it is worth, and sad, to point out that these contributions arise exclusively from the tireless passion of young researchers, whose work is neither recognized nor supported not only by Italian health and biomedical research institutions but often even by the general population.

Francesco Retta


See also:



Rigamonti Daniele. Cavernous Malformations of the Nervous System. Cambridge University Press, 2011.

J Sports Med Phys Fitness. 2014 Mar 18. [Epub ahead of print]
Professional athletes and cerebral cavernomas: an obstacle to overcome.
Fontanella MM, Panciani PP, Spena G, Roca E, Migliorati K, Ambrosi C, Sturiale CL, Retta SF.

Free Radic Biol Med. 2014 Mar;68:134-47.
KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun.
Luca Goitre, Elisa De Luca, Stefano Braggion, Eliana Trapani, Michela Guglielmotto, Fiorella Biasi, Marco Forni, Andrea Moglia, Lorenza Trabalzini, and S. Francesco Retta

Nature. 2013 Jun 27;498(7455):492-6.
EndMT contributes to the onset and progression of cerebral cavernous malformations.
Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, Tournier-Lasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E.

Biochem Biophys Res Commun. 2013 Aug 16;438(1):90-6.
miR-21 coordinates tumor growth and modulates KRIT1 levels.
Orso F, Balzac F, Marino M, Lembo A, Retta SF, Taverna D.

Clin Genet. 2013 Jan;83(1):7-14.
Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management.
Bacigaluppi S, Retta SF, Pileggi S, Fontanella M, Goitre L, Tassi L, La Camera A, Citterio A, Patrosso MC, Tredici G, Penco S.

PLoS One. 2012;7(9):e44705.
Identification of the Kelch family protein Nd1-L as a novel molecular interactor of KRIT1.
Guazzi P, Goitre L, Ferro E, Cutano V, Martino C, Trabalzini L, Retta SF.

J Signal Transduct. 2012;2012:534029.
Reactive oxygen species: friends and foes of signal transduction.
Retta SF, Chiarugi P, Trabalzini L, Pinton P, Belkin AM.

J Signal Transduct. 2012;2012:807682.
Molecular Crosstalk between Integrins and Cadherins: Do Reactive Oxygen Species Set the Talk?
Goitre L, Pergolizzi B, Ferro E, Trabalzini L, Retta SF.

J Signal Transduct. 2012;2012:365769.
The Interplay between ROS and Ras GTPases: Physiological and Pathological Implications.
Ferro E, Goitre L, Retta SF, Trabalzini L.

Brain Pathol. 2011 Mar;21(2):215-24.
Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation.
D'Angelo R, Marini V, Rinaldi C, Origone P, Dorcaratto A, Avolio M, Goitre L, Forni M, Capra V, Alafaci C, Mareni C, Garrè C, Bramanti P, Sidoti A, Retta SF, Amato A.

Metab Eng. 2010 May;12(3):223-32.
Production of novel antioxidative phenolic amides through heterologous expression of the plant's chlorogenic acid biosynthesis genes in yeast.
Moglia A, Comino C, Lanteri S, de Vos R, de Waard P, van Beek TA, Goitre L, Retta SF, Beekwilder J.

PLoS One. 2010 Jul 26;5(7):e11786.
KRIT1 regulates the homeostasis of intracellular reactive oxygen species.
Goitre L, Balzac F, Degani S, Degan P, Marchi S, Pinton P, Retta SF.

Exp Cell Res. 2009 Jan 15;315(2):285-303.
Structural and functional differences between KRIT1A and KRIT1B isoforms: a framework for understanding CCM pathogenesis.
Francalanci F, Avolio M, De Luca E, Longo D, Menchise V, Guazzi P, Sgrò F, Marino M, Goitre L, Balzac F, Trabalzini L, Retta SF.

For updated information on this topic, please visit CCM Italia and Associazione Italiana Angiomi Cavernosi (AIAC) websites.

Ultimo aggiornamento Lunedì 24 Novembre 2014 09:10