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.

Myelin repair stimulated by CNS-selective thyroid hormone action

“…Oral dosing with sobetirome-fortified chow in a previous study resulted in the predicted systemic drug exposure and was effective for delivering sobetirome to the CNS and inducing thyromimetic action (24). The dose of sobetirome (nominal 80 μg/kg/d) was empirically determined previously to be the highest tolerated dose of chowadministered sobetirome (24). A clinical scoring system was used to assess motor disability (32), and mice receiving sobetirome had a faster improvement in clinical scores relative to the control mice ( Figure 4A).…”

“…To evaluate the effects of sobetirome, iCKO-Myrf mice were provided ad lib access to chow containing sobetirome starting at 2 weeks after tamoxifen induction for the remaining 22-week duration of the experiment. Oral dosing with sobetirome-fortified chow in a previous study resulted in the predicted systemic drug exposure and was effective for delivering sobetirome to the CNS and inducing thyromimetic action (24). The dose of sobetirome (nominal 80 μg/kg/d) was empirically determined previously to be the highest tolerated dose of chowadministered sobetirome (24).…”

“…In contrast, sobetirome is a clinical stage experimental thyromimetic therapy that can access the CNS to exert transcriptional and biochemical effects (22,24) via agonist action at TRs (19), which are known to be involved in myelination (3,7). Sob-AM2 is a novel prodrug of sobetirome that when dosed systemically leads to increased CNS distribution and decreased peripheral exposure of the parent drug sobetirome.…”

“…Sobetirome is a clinical-stage thyromimetic devoid of the adverse effects associated with hyperthyroidism and unique among thyromimetics for its ability to cross the blood-brain barrier and distribute to the CNS from a systemic dose (20,21). Sobetirome has been shown to stimulate TH actions during brain development (22,23) and alter brain lipid biomarkers in a model of X-linked adrenoleukodystrophy (24). The increased safety margin of sobetirome compared with TH arises from a combination of differential tissue distribution and specificity for TRβ over TRα (19).…”

Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples

“…Sobetirome (GC-1) is currently being investigated as a therapy for a range of neurological diseases [52]. Few thyromimetics partition to the central nervous system, so it is critical to understand its distribution, so a robust and reproducible bioanalytical technique is necessary to probe its pharmacokinetic properties.…”