Inhalation of the Novel Tryptophan Hydroxylase 1 Inhibitor TPT-004 Alleviates Pulmonary Arterial Hypertension.

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.