Novel therapeutic approaches to ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is considered the prototype of DNA-defect repair (DDR) syndrome, associated with mutations in the ataxia telangiectasia mutated (ATM) gene, also expressed in Purkinje cells and therefore, characterized by progressive neurodegenerative process, especially affecting the cerebellum, increased susceptibility to ionising radiation (IR) and predisposition to cancer in addition to immunodeficiency. The quality of life in A-T patients is dramatically affected by neurological phenotype characterized by ataxia, which make severe the clinical course of diseases, confining these patients to wheelchair from the age of 10. Unfortunately, currently there is no effective treatment to cure or prevent the progress of A-T, but only supportive care of neurological symptoms and the exit usually occurs during about the second or third decade of life. The aim of the thesis was to study the effects of steroid treatment with betamethasone in patients affected with Ataxia-Telangiectasia and to define the potential biochemical and molecular mechanisms of glucocorticoid action examining the role of oxidative stress in its beneficial therapy and the role of genes whose expression is increased after therapy with CCS as glucocorticoid-induced leucine zipper (GILZ) and glucocorticoid receptor (GR). A remarkable improvement of neurological symptoms following a steroid therapy with betamethasone was observed in six A-T patients. Surprisingly, it was inversely correlated with the severity of cerebellar atrophy and the age of A-T patients. Moreover, the steroid therapy with betamethasone was also effective in A-T at a minimal dosage and GILZ may be a useful biomarker of the clinical response. In conclusion, our study documents a beneficial effect of steroids and proves its effectiveness at a very low dosage. This would open a new window of intervention in this so far non-curable disease.