APTEEUS, Campus Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59000 Lille, France.
Neuroradiology Department, Centre Hospitalier Universitaire de Lille, Roger Salengro Hospital, 59000 Lille, France.
Mol Genet Metab. 2024 Nov;143(3):108581. doi: 10.1016/j.ymgme.2024.108581. Epub 2024 Sep 28.
Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.
酰基辅酶 A 氧化酶 1（ACOX1）缺乏症（MIM 264470）是一种常染色体隐性疾病，其特征是酰基辅酶 A 向 2-反式烯酰基辅酶 A 的去饱和作用受损，这是过氧化物酶体中长链脂肪酸（VLCFA）β-氧化分解的第一步。VLCFA 在包括大脑在内的多个器官中的有害积累是该疾病的一个关键生化特征，具有破坏性的神经后果。ACOX1 缺乏症是超罕见的；因此，很少有研究致力于确定症状的主要原因或发现新的治疗方法。当遇到这样一个病例时，我们决定将药物发现工具带到患者床边，试图找到治愈方法。对一名患有 ACOX1 缺乏症的年轻患者进行了皮肤活检，随后应用筛选技术和质谱分析技术设计了一种细胞测定法，使我们能够直接测量小分子对患者原代成纤维细胞的影响。这种方法特别适用于 ACOX1 缺乏症等遗传性代谢疾病。通过评估专有的可重定位药物库，我们发现驱虫药尼氯硝唑可显著减少体外 VLCFA。随后，该药物给患者服用了六年多。本研究概述了筛选和药物选择过程。此外，我们还介绍了全面的临床和生化发现，这些发现有助于了解患者的自然病史和分析患者在整个治疗期间症状的进展。尽管与 ACOX1 缺乏症严重早发型病例的平均死亡年龄相比，患者的总生存期有所延长，但我们在尼氯硝唑治疗期间并未观察到任何明确的临床或生化改善证据。尽管如此，我们的研究显示了长期尼氯硝唑治疗在罕见神经退行性疾病儿童中的良好安全性，并说明了个体化治疗策略在遗传性代谢疾病管理中的潜力，这将使患者和更广泛的科学和医学界受益。
