Efficacy and safety of N-acetyl-L-leucine in patients with ataxia telangiectasia: A randomized, double-blind, placebo-controlled, crossover clinical trial

Mehran Beyraghi-Tousi; Amirhosein Sahebkar; Mahsa Houra; Pooria Sarvghadi; Tannaz Jamialahmadi; Reza Bagheri; Shima Tavallaie; Eric Gumpricht; Maryam Saberi-Karimian

doi:10.1016/j.ejpn.2024.04.009

Efficacy and safety of N-acetyl-L-leucine in patients with ataxia telangiectasia: A randomized, double-blind, placebo-controlled, crossover clinical trial

Eur J Paediatr Neurol. 2024 Apr 22:50:57-63. doi: 10.1016/j.ejpn.2024.04.009. Online ahead of print.

Authors

Mehran Beyraghi-Tousi¹, Amirhosein Sahebkar², Mahsa Houra³, Pooria Sarvghadi⁴, Tannaz Jamialahmadi⁵, Reza Bagheri⁶, Shima Tavallaie⁷, Eric Gumpricht⁸, Maryam Saberi-Karimian⁹

Affiliations

¹ Department of Pediatric Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
² Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
³ Department of Midwifery, School of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran.
⁴ Atiyeh Rehabilitation Center, Mashhad, Iran.
⁵ Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁶ Lung Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷ Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸ Isagenix International, LLC, Gilbert, AZ, 85297, USA.
⁹ Lung Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: saberikm@mums.ac.ir.

PMID: 38669738
DOI: 10.1016/j.ejpn.2024.04.009

Abstract

Background: Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder. Most patients have progressive cerebellar ataxia, oculocutaneous telangiectasia, frequent pulmonary infection, and an increased risk of malignancies. Although N-acetyl-dl-leucine (ADLL) has shown some efficacy in patients with AT, its more pharmacologically active enantiomer, N-acetyl-l-leucine (NALL), has just recently been investigated in ataxic individuals. The current study assessed the efficacy of NALL in patients with AT.

Methods: This 2 × 2 crossover, double-blind, randomized clinical trial was conducted on 20 patients with AT. After excluding four patients, 16 subjects (eight females, eight males; mean age 9.8 ± 3.5 years) with a definitive genetic diagnosis of AT were randomly assigned to one of two study groups, with one group receiving 1-4 g/day NALL or a placebo for six weeks. Subjects then had a 4-week washout before crossing over to the other treatment for an additional six weeks. The Spinocerebellar Ataxia Functional Index (SCAFI) and the Scale for Assessment and Rating of Ataxia (SARA) score assessed patients' motor function. Quality of life (QOL) was evaluated by a specialist using the PedsQL questionnaire. Fasting blood samples were taken from all subjects before and after each intervention to determine potential side effects.

Results: Although patients' nausea and constipation were improved, the results failed to reveal any significant benefits of NALL treatment on ataxia symptoms. NALL treatment had no significant effects on SARA, SCAFI-9HPT (9-hole peg test) nondominant, SCAFI-9HPT dominant, or SCAFI-8WMT (8 m walking time) (p > 0.05). Our patient's Physical Health score in Child self-report and Parent proxy-report did not significantly change in the treatment group compared to the placebo (p > 0.05). Furthermore, there were no significant changes in energy and macronutrient intake after NALL treatment. None of the volunteers reported serious or moderate side effects.

Conclusions: To the best of our knowledge, this was the first placebo-controlled, randomized clinical trial exploring NALL's potential effects for treating AT. Despite improvements in some symptomss, NALL intervention failed to improve motor function significantly. However, patients' nausea and constipation were improved by NALL, which can be a relevant benefit clinically.

Keywords: ATM; Ataxia telangiectasia; Clinical trial; N-acetyl-leucine.