Drug discovery for X‐linked adrenoleukodystrophy: An unbiased screen for compounds that lower very long‐chain fatty acids
| العنوان: | Drug discovery for X‐linked adrenoleukodystrophy: An unbiased screen for compounds that lower very long‐chain fatty acids |
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| المؤلفون: | Ann B. Moser, Nancy Braverman, Yanqiu Liu, Ali Fatemi, Shandi Hiebler, Ulrike Schrifl, Paul A. Watkins, Xiaohai Shi, Steven J. Steinberg |
| المصدر: | J Cell Biochem |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Drug, endocrine system, media_common.quotation_subject, Genetic enhancement, Primary Cell Culture, Pharmacology, ATP Binding Cassette Transporter, Subfamily D, Member 1, Biochemistry, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Irbesartan, Drug Discovery, Animals, Humans, Medicine, Adrenoleukodystrophy, Fibroblast, Molecular Biology, Antihypertensive Agents, media_common, Mice, Knockout, business.industry, Fatty Acids, Hematopoietic stem cell, Cell Biology, Fibroblasts, medicine.disease, High-Throughput Screening Assays, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Peripheral neuropathy, Cell culture, 030220 oncology & carcinogenesis, Mutation, lipids (amino acids, peptides, and proteins), business, medicine.drug |
| الوصف: | X-linked adrenoleukodystrophy (XALD) is a genetic neurologic disorder with multiple phenotypic presentations and limited therapeutic options. The childhood cerebral phenotype (CCALD), a fatal demyelinating disorder affecting about 35% of patients, and the adult-onset adrenomyeloneuropathy (AMN), a peripheral neuropathy affecting 40%-45% of patients, are both caused by mutations in the ABCD1 gene. Both phenotypes are characterized biochemically by elevated tissue and plasma levels of saturated very long-chain fatty acids (VLCFA), and an increase in plasma cerotic acid (C26:0), along with the clinical presentation, is diagnostic. Administration of oils containing monounsaturated fatty acids, for example, Lorenzo's oil, lowers patient VLCFA levels and reduced the frequency of development of CCALD in presymptomatic boys. However, this therapy is not currently available. Hematopoietic stem cell transplant and gene therapy remain viable therapies for boys with early progressive cerebral disease. We asked whether any existing approved drugs can lower VLCFA and thus open new therapeutic possibilities for XALD. Using SV40-transformed and telomerase-immortalized skin fibroblasts from an XALD patient, we conducted an unbiased screen of a library of approved drugs and natural products for their ability to decrease VLCFA, using measurement of C26:0 in lysophosphatidyl choline (C26-LPC) by tandem mass spectrometry as the readout. While several candidate drugs were initially identified, further testing in primary fibroblast cell lines from multiple CCALD and AMN patients narrowed the list to one drug, the anti-hypertensive drug irbesartan. In addition to lowering C26-LPC, levels of C26:0 and C28:0 in total fibroblast lipids were reduced. The effect of irbesartan was dose dependent between 2 and 10 μM. When male XALD mice received orally administered irbesartan at a dose of 10 mg/kg/day, there was no reduction in plasma C26-LPC. However, irbesartan failed to lower mouse fibroblast C26-LPC consistently. The results of these studies indicate a potential therapeutic benefit of irbesartan in XALD that should be validated by further study. |
| تدمد: | 1097-4644 0730-2312 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ce4700490ef190546392aabc4c4af17Test https://doi.org/10.1002/jcb.30014Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4ce4700490ef190546392aabc4c4af17 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10974644 07302312 |
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