title: A Thyroid Hormone-Based Strategy for Correcting the Biochemical Abnormality in X-Linked Adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disorder characterized by adrenal insufficiency and central nervous system (CNS) demyelination. All patients with X-ALD have the biochemical abnormality of elevated blood and tissue levels of very long chain fatty acids (VLCFAs), saturated fatty acids with 24 to 26 carbons. X-ALD results from loss of function mutations in the gene encoding the peroxisomal transporter ABCD1, which is responsible for uptake of VLCFAs into peroxisomes for degradation by oxidation. One proposed therapeutic strategy for genetic complementation of ABCD1 is pharmacologic upregulation of ABCD2, a gene encoding a homologous peroxisomal transporter. Here, we show that thyroid hormone or sobetirome, a clinical-stage selective thyroid hormone receptor agonist, increases cerebral Abcd2 and lowers VLCFAs in blood, peripheral organs, and brains of mice with defective Abcd1. These results support an approach to treating X-ALD that involves a thyromimetic agent that reactivates VLCFA disposal both in the periphery and the CNS.
authors.affiliation: Department of Physiology and Pharmacology and Program in Chemical Biology, Oregon Health & Science University, Portland, Oregon 92739.
authors.forename: Meredith D
authors.initials: MD
authors.lastname: Hartley
authors.affiliation: Department of Physiology and Pharmacology and Program in Chemical Biology, Oregon Health & Science University, Portland, Oregon 92739.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Kirkemo
authors.affiliation: Department of Physiology and Pharmacology and Program in Chemical Biology, Oregon Health & Science University, Portland, Oregon 92739.
authors.forename: Tapasree
authors.initials: T
authors.lastname: Banerji
authors.affiliation: Department of Physiology and Pharmacology and Program in Chemical Biology, Oregon Health & Science University, Portland, Oregon 92739.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000085:Acetates / Q000008:administration & dosage / Q000627:therapeutic use*; D000326:Adrenoleukodystrophy / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism; D005347:Fibroblasts; D006801:Humans; D008297:Male; D051379:Mice; D020675:Peroxisomes / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use*; D011988:Receptors, Thyroid Hormone / Q000819:agonists; D013963:Thyroid Hormones / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: C508354:ABCD2 protein, mouse; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D000085:Acetates; D005227:Fatty Acids; C413355:GC 1 compound; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones