Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome

ABSTRACT

Introduction

Ataxia telangiectasia (A-T) is a life-limiting autosomal recessive disease characterized by cerebellar degeneration, ocular telangiectasias, and sinopulmonary disease. Since there is no cure for A-T, the standard of care is primarily supportive.

Areas covered

We review clinical trials available in PubMed from 1990 to 2023 focused on lessening A-T disease burden. These approaches include genetic interventions, such as antisense oligonucleotides, designed to ameliorate disease progression in patients with select mutations. These approaches also include pharmacologic treatments that target oxidative stress, inflammation, and mitochondrial exhaustion, to attenuate neurological progression in A-T. Finally, we discuss the use of biological immunotherapies for the treatment of malignancies and granulomatous disease, along with other supportive therapies being used for the treatment of pulmonary disease and metabolic syndrome.

Expert opinion

Barriers to successful genetic and pharmacologic interventions in A-T include the need for personalized treatment approaches based on patient-specific ATM mutations and phenotypes, lack of an animal model for the neurologic phenotype, and extreme rarity of disease making large-scale randomized trials difficult to perform. Ongoing efforts are needed to diagnose patients earlier, discover more effective therapies, and include more individuals in clinical trials, with the goal to lessen disease burden and to find a cure for patients with A-T.

KEYWORDS:

• Ataxia telangiectasia (A-T)
• ATM
• clinical trial
• biomarker
• genetic intervention

Article highlights

• The current standard of care for Ataxia telangiectasia (A-T), a life-limiting neurologic disease, is primarily supportive.

• Barriers to identifying therapies for A-T include variability in disease phenotype, delayed diagnoses, a lack of clear biomarkers for treatment efficacy, a limited understanding of the basis for neurologic damage, the rarity of the disease, and the lack of an animal model that mimics the human neurologic disease.

• Potential genetic interventions that may be useful in treating A-T include antisense oligo nucleotides and adeno-associated viral vectors.

• Pharmacologic treatments that target oxidative stress, inflammation, and mitochondrial exhaustion may provide neurologic benefit in A-T.

• Treatment of malignancies is especially difficult in patients with A-T, but new biologics show promise in treating hematologic malignancies.

• In order to develop treatments for A-T, we must continue to study the natural history of the disease, investigate polygenic factors that influence disease phenotype, and conduct randomized, placebo-controlled, double-blinded studies of potential therapeutics.

Declaration of interest

H Lederman declares being a consultant to EryDel and has received payment for his consultancy. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This manuscript was funded by the National Institutes of Health (Bethesda, MD, USA) (SAM: R01 HL114800), R01 FD007605 (SAM, HML), A-T Children’s Project (SAM, HML).