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Highlights d CNS-penetrating thyromimetic prodrug Sob-AM2 is better tolerated in chronic dosing d Sob-AM2 is more effective than sobetirome at lowering C26:0 in the CNS d VLCFA reduction in the CNS is limited by slow CNS lipid turnover

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. We report here that TREM2 is a thyroid hormone regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone. Both endogenous thyroid hormone and sobetirome, a synthetic thyroid hormone agonist drug, suppress pro-inflammatory cytokine production from myeloid cells including macrophages that have been treated with the SARS-CoV-2 spike protein which produces a strong, pro-inflammatory phenotype. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia, a phenotype consistent with activation of the TREM2 pathway. The thyroid hormone antagonist NH-3 blocks the anti-inflammatory effects of thyroid hormone agonists and suppresses microglia phagocytosis. Finally, in a murine experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model, treatment with Sob-AM2, a CNS-penetrating sobetirome prodrug, results in increased Trem2 expression in disease lesion resident myeloid cells which correlates with therapeutic benefit in the EAE clinical score and reduced damage to myelin. Our findings represent the first report of endocrine regulation of TREM2 and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small molecule therapeutic agents.

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