Myelin repair stimulated by CNS-selective thyroid hormone action

Hartley, Meredith D.; Banerji, Tania; Tagge, Ian J.; Kirkemo, Lisa L.; Chaudhary, Poras; Calkins, Evan; Galipeau, Danielle; Shokat, Mitra D.; DeBell, Margaret J.; Leuven, Shelby Van; Miller, Hannah; Marracci, Gail; Pocius, Edvinas; Banerji, Tapasree; Ferrara, Skylar J.; Meinig, J. Matthew; Emery, Ben; Bourdette, Dennis; Scanlan, Thomas S.

doi:10.1172/jci.insight.126329

Cited by 71 publications

(70 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the CNS, we observed that 12 weeks of Sob-AM2 treatment induced up to 40% lowering of C26-LPC and 15-20% lowering of total C26:0 with no weight loss. We have also shown recently in a separate study that sobetirome and Sob-AM2 are effective myelin repair agents (Hartley et al, 2019). This occurs through a mechanism involving thyromimetic induced oligodendrogenesis which is a potentially complementary therapeutic effect to VLCFA lowering in X-ALD.…”

Section: Discussionmentioning

confidence: 67%

Pharmacological complementation remedies an inborn error of lipid metabolism

Hartley

Shokat

DeBell

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 67%

Pharmacological complementation remedies an inborn error of lipid metabolism

Hartley

Shokat

DeBell

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, during the oligodendrogenesis promoted by GC-1, TRβ1 was shown to be upregulated. Finally, the same group demonstrated that it was possible to show and monitor the GC-1 induced oligodendrogenesis in the corpus callosum, occipital cortex and optic nerve using an in-vivo transgenic mouse model ( 73 , 84 ).…”

Section: Sobetirome and Novel Diphenylmethane Structure Based Thyromimentioning

confidence: 99%

“…Since a concomitant decrease of circulating T4 and T3 was also observed in the same animal model, the potential for Sob-AM2 to address the cerebral hypothyroidism and the peripheral hyperthyroidism characteristic of MCT8 deficiency has been consistently suggested ( 86 ). Using iCKO-Myrf mice, a recently developed genetic mouse model of demyelination and remyelination, where demyelination was induced by tamoxifen treatment of adult Myrf fl / fl ; Plp1-CreERT mice Hartley et al ( 73 ) and Koenning et al ( 87 ) demonstrated that chronic treatment with Sobetirome (80 μg/kg/d, p.o.) or Sob-AM2 (84 μg/kg/d, p.o.)…”

Section: Sobetirome and Novel Diphenylmethane Structure Based Thyromimentioning

confidence: 99%

Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders

et al. 2020

View full text Add to dashboard Cite

Thyroid hormones (THs) elicit significant effects on numerous physiological processes, such as growth, development, and metabolism. A lack of thyroid hormones is not compatible with normal health. Most THs effects are mediated by two different thyroid hormone receptor (TR) isoforms, namely TRα and TRβ, with the TRβ isoform known to be responsible for the main beneficial effects of TH on liver. In brain, despite the crucial role of TRα isoform in neuronal development, TRβ has been proposed to play a role in the remyelination processes. Consequently, over the past two decades, much effort has been applied in developing thyroid hormone analogs capable of uncoupling beneficial actions on liver (triglyceride and cholesterol lowering) and central nervous system (CNS) (oligodendrocyte proliferation) from deleterious effects on the heart, muscle and bone. Sobetirome (GC-1) and subsequently Eprotirome (KB2115) were the first examples of TRβ selective thyromimetics, with Sobetirome differing from the structure of thyronines because of the absence of halogens, biaryl ether oxygen, and amino-acidic side chain. Even though both thyromimetics showed encouraging actions against hypercholesterolemia, non-alcoholic steatohepatitis (NASH) and in the stimulation of hepatocytes proliferation, they were stopped after Phase 1 and Phase 2–3 clinical trials, respectively. In recent years, advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit TR isoform-selective binding, and/or liver- and tissue-selective uptake, with Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) probably representing two of the most promising lipid lowering agents, currently under phase 2–3 clinical trials. More recently the application of a comprehensive panel of ADME-Toxicity assays enabled the selection of novel thyromimetic IS25 and its prodrug TG68, as very powerful lipid lowering agents both in vitro and in vivo . In addition to dyslipidemia and other liver pathologies, THs analogs could also be of value for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS). Sob-AM2, a CNS- selective prodrug of Sobetirome has been shown to promote significant myelin repair in the brain and spinal cord of mouse demyelinating models and it is rapidly moving into clinical trials in humans. Taken together all these findings support the great potential of selective thyromimetics in targeting a large variety of human pathologies characterized by altered metabolism and/or cellular differentiation.

show abstract

“…RTH␤ and MCT8 deficiency) to more common diseases (e.g. multiple sclerosis, hypercholesterolemia and NASH) [2,8,[24][25][26][27]. Rational design of thyroid hormone analogues with appropriate preclinical studies should pave the way for clinical trials in populations with rare and common disorders.…”

Section: Perspectivesmentioning

confidence: 99%

Therapeutic applications of thyroid hormone analogues

Visser

2021

Annales d'Endocrinologie

View full text Add to dashboard Cite

Cellular thyroid hormone homeostasis requires adequate function of: (1) thyroid hormone transporter proteins at the plasma membrane, (2) deiodinating enzymes and (3) nuclear thyroid hormone receptors (TRs). Defects in any of these processes give rise to distinct disease entities, collectively called thyroid hormone signaling disorders. Thyroid hormone analogues hold therapeutic potential in thyroid hormone signaling disorders by bypassing defective transporters or binding to mutant TRs. This review will focus on the application of analogues in thyroid hormone signaling disorders, particularly monocarboxylate transporter (MCT)8 deficiency, and resistance to thyroid hormone due to mutations in TR␤ (RTH␤)

show abstract

Myelin repair stimulated by CNS-selective thyroid hormone action

Cited by 71 publications

References 59 publications

Pharmacological complementation remedies an inborn error of lipid metabolism

Pharmacological complementation remedies an inborn error of lipid metabolism

Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders

Therapeutic applications of thyroid hormone analogues

Contact Info

Product

Resources

About