Progress and prospects for treating ataxia telangiectasia

ABSTRACT

Introduction: Ataxia Telangiectasia (AT) is an autosomal recessive disorder due to mutations in the ATM gene (11q22.3), which encodes a kinase, which initiates and propagates the cellular response to severe DNA lesions. Cerebellar ataxia, ocular and skin telangiectasia, immunodeficiency, cardiovascular, liver and endocrine defects, and predisposition to malignancies characterize the classical form of AT. Milder forms and AT-like disorders (ATLD) have later onset or slower progression. ATM carriers are at increased risk for cancer and other diseases.

Areas covered: We reviewed the most updated treatments of AT from 2014. A proactive monitoring and early treatment of respiratory manifestations, growth, nutrition, cardiovascular defects, liver and metabolism and oxidative stress, are the most challenging issues. Steroids improved neurodegeneration with some limitations. The alternative roles of the ATM kinase in cell homeostasis via signalling pathways [e.g. mTORC1, Akt, ROS, PDGFRB] control, nuclear (in developing cells) vs. cytoplasmic functions (in post-mitotic cells) are reviewed.

Expert opinion: AT demands a multidisciplinary specialized model of care aided by pharmacological and non-pharmacological interventions. Dexamethasone (clinically) and ibuprofen (experimentally) received positive assessment for neurological and inflammatory disturbances. Gene and stem cell therapies are in progress.

KEYWORDS:

• Ataxia telangiectasia
• new treatments
• gene therapy
• stem cell therapy
• dexamethasone
• ibuprofen
• riluzole
• varenicline
• N-acetyl-L-Leucine
• deep brain stimulation

Article highlights

• The ATM protein kinase plays two main roles: (1) in mitotic/proliferating cells, it acts as the chief mobilizer and sensor responsible for the initiation and propagation of nuclear signals to cell cycle checkpoints, which activate the cellular machinery responsible to repair severe DNA lesions [DNA damage repair, DDR]; and (2) in post-mitotic, non-proliferating cells, it controls cellular homeostasis through alternative cytoplasmic [e.g. mitochondrial, peroxisomal, and vesicular] cell-signalling pathways [e.g. eIF4E‐binding protein 1, HDAC4, mTORC1, Akt, ROS/oxidation, PDGFRB];

• The cytoplasmic roles of ATM serine/threonine kinase, which take place prevalently in post-mitotic cells (i.e. neurons; non-replicating immune-mediated cells) and are mostly related to oxidative stress mechanisms and metabolism, seem to better explain neurodegeneration, growth and nutritional defects, premature ageing, and systemic involvement in AT, allowing alternative therapeutic approaches;

• Proactive monitoring and early treatment of respiratory and immune dysregulation, growth and nutritional deficits, inflammation, cardiovascular disease, liver and metabolic abnormalities, neurological impairment and oxidative stress, are the newest targets aimed to slow the process of disease progression and degeneration in AT;

• AT demands a multidisciplinary specialized model of care aided by pharmacological and non-pharmacological interventions;

• Desamethasone (clinically) and ibuprofen (experimentally) received positive assessment for neurological and inflammatory disturbances, respectively; glutamine supplementation and NAD+ replenishment, use of Rad3-related (ATR) inhibitors and deep brain stimulation are additional promising (experimental and clinical) therapeutic strategies.

• Drugs imported from trials on hereditary cerebellar ataxias (e.g. varenicline, riluzole, and N-acetyl-L-Leucine) are under study in AT patients; allogenic haematopoietic stem cell therapy and gene therapies are also in progress.

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Acknowledgments

We wish to thank prof. Rosemary Reidy (scientific lecturer, University of Catania, Italy) for revising and editing the manuscript. Professor Luciana Chessa is retired professor of Medical Genetics, currently at the Sapienza University of Rome Foundation, Rome, Italy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.