Inhalation of the novel tryptophan hydroxylase 1 inhibitor TPT-004 alleviates pulmonary arterial hypertension

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Item Type:	Article
Title:	Inhalation of the novel tryptophan hydroxylase 1 inhibitor TPT-004 alleviates pulmonary arterial hypertension
Creators Name:	Legchenko, E., Chouvarine, P., Hysko, K., Qadri, F., Wesolowski, R., Specker, E., Glage, S., Meier, M., Schwarz, K., Heineke, J., Pohlmann, G., Ramazanoglu, M., Bader, M. and Hansmann, G.
Abstract:	Inhaled pharmacotherapies are promising treatment options for patients with pulmonary arterial hypertension (PAH), as they minimize extrapulmonary adverse effects. Recently, we developed a highly specific tryptophan hydroxylase 1 inhibitor (TPHi): TPT-004. We hypothesized that repetitive nose-only inhalation of TPT-004 alleviates PAH and pulmonary vascular remodeling in the Sugen 5416/hypoxia (SuHx) rat model. Male Sprague Dawley rats were divided into three groups: ConNx (control animals kept in room air during the study); SuHx+vehicle (rats injected with the VEGFR2 inhibitor SU5416 and then exposed to chronic hypoxia for 3 weeks, followed by 10 days recovery and subsequent 4 weeks of daily vehicle inhalations; and SuHx+TPHi (SuHx-exposed rats after recovery treated with daily inhalations of the TPH1 inhibitor, TPT-004, for 4 weeks). Closed-chest right–left heart catheterization and cardiac magnetic resonance imaging were performed in spontaneously breathing rats. Histological and mRNA-sequencing analyses were performed on lungs. SuHx-exposed rats had severe PAH, right ventricle (RV) hypertrophy, and RV dilation. In comparison with SuHx-exposed rats, TPHi-treated SuHx rats had significantly lower RV systolic pressure (67.25 vs. 51.47 mm Hg; P < 0.0001), normalized RV end-systolic volume (182.6 vs. 105.1 μl; P < 0.0001), and improved RV ejection fraction by cardiac magnetic resonance imaging (47.9 vs. 66.8%; P < 0.0001). Inhaled TPT-004 did not affect left ventricular (LV) end-diastolic or systemic blood pressure. TPT-004 therapy reversed pulmonary vascular remodeling and alveolar macrophage infiltration. RNA sequencing unraveled TPHi-induced changes in pulmonary gene expression: increased cell adhesion as well as reduced cell motility and migration; suppressed extracellular matrix remodeling; modulated immune response; and suppressed pulmonary vascular remodeling by means of modulating proliferation, apoptosis, and homeostasis. Taken together, TPT-004 is an effective therapeutic PAH agent that does not cause any hemodynamic adverse effects in rodents, and thus, should be tested further towards a clinical phase 1b/phase 2 study in patients with PAH.
Keywords:	Pulmonary Hypertension, Serotonin, Inhaled Therapy, Pulmonary Vascular Disease, Tryptophan Hydroxylase Inhibitor, Animals, Rats
Source:	American Journal of Respiratory Cell and Molecular Biology
ISSN:	1044-1549
Publisher:	American Thoracic Society
Volume:	73
Number:	2
Page Range:	288-298
Date:	August 2025
Official Publication:	https://doi.org/10.1165/rcmb.2024-0365oc
PubMed:	View item in PubMed

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