Current and future therapeutic strategies to treat ataxia telangiectasia

Abstract

Introduction: Ataxia telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, hypersensitivity to ionizing radiation, and predisposition to malignancy. AT is caused by mutations in ataxia telangiectasia mutated (ATM) gene encoding ATM, a protein kinase responsible of DNA damage response and cell cycle control. Patients with the classical form of AT survive until the second-third decade of life; the major cause of death are lung disease due to recurrent sinopulmonary infections and cancer (T-cell leukemia and lymphoma). Treatment of primary manifestations of AT has been so far unsuccessful. Early and continued physical therapy, IVIG replacement and antibiotic treatments reduce number and severity of infections prolonging the lifespan of patients. Recently, dopaminergic drugs were shown to improve the control of movement disorders and steroids were demonstrated to dramatically reduce the neurological features.

Areas covered: Clinical and molecular aspects of AT as well as pathogenesis, differential diagnosis and current treatments are summarized.

Expert opinion: Efficacy of steroids in improving ataxia of AT patients is proven. To avoid the side effects of long-term administration of steroids, encapsulation of the drug into erythrocytes followed by slow release appears promising. Moreover, extrapyramidal symptoms may be ameliorated by dopaminergic drugs. Long-term, placebo-controlled studies are needed for these treatments.

Keywords::

• antioxidants
• ataxia telangiectasia
• ataxia-telangiectasia mutated gene
• ataxia-telangiectasia mutated protein
• dopaminergic drugs
• read-through compounds
• steroids

Acknowledgements

A special thank-you to all the AT patients. I have had the luck to encounter in these years: masters of life and science. Thanks also to all the colleagues, mentors and collaborators, who have shared their knowledge with me: a list too long to write here. Finally, thanks to the institutions, private funders and AT family associations who have supported my work.

Notes

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