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1.
Cell Chem Biol ; 27(5): 551-559.e4, 2020 05 21.
Article in English | MEDLINE | ID: mdl-32169163

ABSTRACT

X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disease in which increased very long chain fatty acids (VLCFAs) in the central nervous system (CNS) cause demyelination and axonopathy, leading to neurological deficits. Sobetirome, a potent thyroid hormone agonist, has been shown to lower VLCFAs in the periphery and CNS. In this study, two pharmacological strategies for enhancing the effects of sobetirome were tested in Abcd1 KO mice, a murine model with the same inborn error of metabolism as X-ALD patients. First, a sobetirome prodrug (Sob-AM2) with increased CNS penetration lowered CNS VLCFAs more potently than sobetirome and was better tolerated with reduced peripheral exposure. Second, co-administration of thyroid hormone with sobetirome enhanced VLCFA lowering in the periphery but did not produce greater lowering in the CNS. These data support the conclusion that CNS VLCFA lowering in Abcd1 knockout mice is limited by a mechanistic threshold related to slow lipid turnover.


Subject(s)
Acetates/therapeutic use , Adrenoleukodystrophy/drug therapy , Phenols/therapeutic use , Prodrugs/therapeutic use , Thyroid Hormones/therapeutic use , ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics , Adrenoleukodystrophy/genetics , Adrenoleukodystrophy/metabolism , Animals , Disease Models, Animal , Fatty Acids/metabolism , Female , Humans , Lipid Metabolism, Inborn Errors/drug therapy , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/metabolism , Male , Mice , Mice, Knockout
2.
JCI Insight ; 4(8)2019 04 18.
Article in English | MEDLINE | ID: mdl-30996143

ABSTRACT

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.


Subject(s)
Acetates/pharmacology , Multiple Sclerosis/drug therapy , Myelin Sheath/drug effects , Phenols/pharmacology , Thyroid Hormones/agonists , White Matter/drug effects , Acetates/therapeutic use , Animals , Axons/drug effects , Axons/pathology , Cell Differentiation/drug effects , Disease Models, Animal , Female , Gene Knockdown Techniques , Gliotoxin/toxicity , Humans , Magnetic Resonance Imaging , Male , Mice , Mice, Transgenic , Multiple Sclerosis/etiology , Multiple Sclerosis/pathology , Myelin Sheath/pathology , Oligodendroglia/drug effects , Oligodendroglia/pathology , Phenols/therapeutic use , Prodrugs/pharmacology , Prodrugs/therapeutic use , Remyelination/drug effects , Remyelination/genetics , Thyroid Hormones/administration & dosage , Transcription Factors/genetics , White Matter/cytology , White Matter/diagnostic imaging , White Matter/pathology
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