Novel Tryptophan Hydroxylase Inhibitor TPT-001 Reverses PAH, Vascular Remodeling, and Proliferative-Proinflammatory Gene Expression

• Published in: JACC. Basic to translational science Vol. 9; no. 7; pp. 890 - 902
• Main Authors: Legchenko, Ekaterina, Chouvarine, Philippe, Qadri, Fatimunnisa, Specker, Edgar, Nazaré, Marc, Wesolowski, Radoslaw, Matthes, Susann, Bader, Michael, Hansmann, Georg
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2024; Elsevier
• Subjects: Cardiovascular; drug discovery; Original Research - Preclinical; pulmonary arterial hypertension; serotonin; tryptophan hydroxylase inhibitor; TPH1; tryptophan hydroxylase inhibitor; RV; RVEDP; RVSP; LV; PA; serotonin; DEGs; drug discovery; SuHx; PAH; ROS; PH; TPHi; pulmonary arterial hypertension; PASMC; PVD; pulmonary artery; left ventricle; tryptophan hydroxylase 1; pulmonary hypertension; right ventricular systolic pressure; pulmonary vascular disease; inhibitor of tryptophan hydroxylase 1; right ventricular end-diastolic pressure; pulmonary arterial smooth muscle cells; reactive oxygen species; differentially expressed genes; right ventricle; Sugen/hypoxia
• DOI: 10.1016/j.jacbts.2024.04.006
• ISSN: 2452-302X

[Display omitted] •Peripheral serotonin, synthesized by the enzyme TPH1, is a pathogenic factor in PAH.•Oral TPT-001, a novel class drug of TPHi, reverses severe PAH and prevents associated RV dysfunction in the clinically relevant SuHx rat model of PAH.•TPT-001 suppresses perivascular infiltration of CD3+ T cells, proinflammatory F4/80+/CD68+ macrophages, and PCNA+ alveolar epithelial cells, found in the SuHx PAH rat lung.•Lung mRNA-sequencing unraveled distinct gene expression patterns in SuHx-rat lungs related to PASMC proliferation, reactive oxygen species, inflammation, and vasodilation, all of which are beneficially affected by the oral TPH1-inhibitor TPT-001.•TPH1 inhibitors are promising options for oral or inhalative treatment of PAH, and should be studied in clinical trials. The serotonin pathway has long been proposed as a promising target for pulmonary arterial hypertension (PAH)—a progressive and uncurable disease. We developed a highly specific inhibitor of the serotonin synthesizing enzyme tryptophan hydroxylase 1 (TPH1), TPT-001 (TPHi). In this study, the authors sought to treat severe PAH in the Sugen/hypoxia (SuHx) rat model with the oral TPHi TPT-001. Male Sprague Dawley rats were divided into 3 groups: 1) ConNx, control animals; 2) SuHx, injected subcutaneously with SU5416 and exposed to chronic hypoxia for 3 weeks, followed by 6 weeks in room air; and 3) SuHx+TPHi, SuHx animals treated orally with TPHi for 5 weeks. Closed-chest right- and left heart catheterization and echocardiography were performed. Lungs were subject to histologic and mRNA sequencing analyses. Compared with SuHx-exposed rats, which developed severe PAH and right ventricular (RV) dysfunction, TPHi-treated SuHx rats had greatly lowered RV systolic (mean ± SEM: 41 ± 2.3 mm Hg vs 86 ± 6.5 mm Hg; P < 0.001) and end-diastolic (mean ± SEM: 4 ± 0.7 mm Hg vs 14 ± 1.7 mm Hg; P < 0.001) pressures, decreased RV hypertrophy and dilation (all not significantly different from control rats), and reversed pulmonary vascular remodeling. We identified perivascular infiltration of CD3+ T cells and proinflammatory F4/80+ and CD68+ macrophages and proliferating cell nuclear antigen–positive alveolar epithelial cells all suppressed by TPHi treatment. Whole-lung mRNA sequencing in SuHx rats showed distinct gene expression patterns related to pulmonary arterial smooth muscle cell proliferation (Rpph1, Lgals3, Gata4), reactive oxygen species, inflammation (Tnfsrf17, iNOS), and vasodilation (Pde1b, Kng1), which reversed expression with TPHi treatment. Inhibition of TPH1 with a new class of drugs (here, TPT-001) has the potential to attenuate or even reverse severe PAH and associated RV dysfunction in vivo by blocking the serotonin pathway.