Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism

Meredith D. Hartley, Mitra D. Shokat, Margaret J. DeBell, Tania Banerji, Lisa L. Kirkemo, Thomas S. Scanlan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)551-559.e4
JournalCell Chemical Biology
Volume27
Issue number5
DOIs
StatePublished - May 21 2020

Keywords

  • CNS lipids
  • X-linked adrenoleukodystrophy
  • demyelination
  • inborn error of metabolism
  • myelin lipids
  • prodrugs
  • thyroid hormone
  • thyromimetics
  • very long chain fatty acids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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