Pharmacological complementation remedies an inborn error of lipid metabolism

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease involving loss of function of the peroxisomal transporter ABCD1, resulting in an inappropriate increase in very long chain fatty acid (VLCFA) concentrations throughout the body. Elevated levels of VLCFAs in the central nervous system (CNS) cause demyelination and axonal degeneration, leading to severe neurological deficits. Sobetirome, a potent thyroid hormone agonist, and other thyromimetics have been shown to lower VLCFA levels. In this study, two pharmacological strategies for enhancing the effects of thyromimetics in the brain were tested. First, a CNS-selective thyromimetic prodrug was used to increase thyromimetic drug exposure in the CNS. Second, thyroid hormone and the thyromimetic were co-administered to increase total thyroid hormone agonism in the CNS. These strategies lowered VLCFAs by up to 60% in the periphery. In the brain and spinal cord, C26/C22 was lowered by 15-20% and C26-LPC by 25-30% in the brain and ~40% in the spinal cord. Co-administration of thyroid hormone with sobetirome led to enhanced VLCFA lowering in the periphery compared to sobetirome alone but did not produce greater lowering in the CNS. The extent of lowering in the brain was limited by a mechanistic threshold related to slow turnover kinetics, which increased thyroid hormone action could not overcome. These findings provide evidence that CNS-penetrating thyromimetics can lower VLCFAs in peripheral organs in addition to the brain and spinal cord, thereby correcting the lipid abnormality associated with X-ALD. Keywordsthyroid hormone, thyromimetics, prodrugs, X-linked adrenoleukodystrophy, demyelination, very long chain fatty acids, myelin lipids, CNS lipids, inborn error of metabolism

Future Advances in Early Phase Clinical Development for Disease Modifying Therapies for Neurodegenerative Diseases

“…93 Finally, an amide prodrug derivative of sobetirome, a selective thyroid receptor β agonist, increased brain penetration and lowered CNS very-long chain fatty acids (VLCFA) compared to the parent compound in an ABCD1 knock-out mouse model for the human disease adrenoleukodystrophy. 94 Adding moieties to centrally acting molecules has proved a successful strategy for increasing brain penetration of molecules not otherwise sufficiently brain penetrant in the past and will continue to do so in the future.…”

A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

“…[10][11] We have used this strategy to increase sobetirome penetration into the CNS with mouse models of demyelination and lipid metabolism. [12][13] This prodrug strategy is underpinned by two pivotal processes and entails (1) converting the drug's carboxylic acid functional group into an N-methyl amide which imparts beneficial physicochemical properties for BBB penetration via passive diffusion. As an amide, (2) the prodrug is a substrate for fatty acid amide hydrolase (FAAH), an amidase with enriched expression in the CNS that cleaves the amide prodrug into the carboxylate-containing parent drug.…”