Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia
Felix Rafael De Bie,
Christopher Gates Halline,
Travis Kotzur,
Kevin Hayes,
Christopher Copeland Rouse,
Jonathan Chang,
Abby Christine Larson,
Sameer Ahmad Khan,
Ashley Spina,
Samantha Tilden,
Francesca Maria Russo,
Holly Lee Hedrick,
Jan Deprest,
Emily Anne Partridge
Affiliations
Felix Rafael De Bie
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, Leuven, Belgium
Christopher Gates Halline
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Travis Kotzur
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Kevin Hayes
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Christopher Copeland Rouse
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Jonathan Chang
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Abby Christine Larson
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Sameer Ahmad Khan
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Ashley Spina
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Samantha Tilden
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Francesca Maria Russo
Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, Leuven, Belgium
Holly Lee Hedrick
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States
Jan Deprest
Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, Leuven, Belgium; Institute of Women's Health, University College London, London, UK
Emily Anne Partridge
Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States; Corresponding author at: 3615 Civic Center Blvd, Suite 1114F, 19104, Philadelphia, PA, United States.
Summary: Background: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. Methods: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. Findings: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure. Interpretation: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH. Funding: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).