Emerging antenatal therapies for congenital diaphragmatic hernia-induced pulmonary hypertension in preclinical models

Abstract

Congenital diaphragmatic hernia (CDH)-related deaths are the largest contributor of in-hospital neonatal deaths in children with congenital malformations. Morbidity and mortality in CDH are directly related to the development of pulmonary hypertension (PH). Current treatment consists of supportive measures. To date, no pharmacotherapy has been shown to effectively reverse the hallmark finding of pulmonary vascular remodeling that is associated with pulmonary hypertension in CDH (CDH-PH). As such, there is a great need for novel therapies to effectively manage CDH-PH. Our review aims to evaluate emerging therapies, and specifically focuses on those that are still under investigation and not approved for clinical use by the Food and Drug Administration. Therapies were categorized into antenatal pharmacotherapies or antenatal regenerative therapies and assessed on their method of administration, safety profile, effect on pulmonary vascular pathophysiology, and overall efficacy. In general, emerging antenatal pharmaceutical and regenerative treatments primarily aim to alleviate pulmonary vascular remodeling by restoring normal function and levels of key regulatory factors involved in pulmonary vascular development and/or in promoting angiogenesis. Overall, while these emerging therapies show great promise for the management of CDH-PH, most require further assessment of safety and efficacy in preclinical models before translation into the clinical setting.

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

“…Several other drugs have demonstrated potential to improve PH-features in different animal models of CDH. 1 , 46 There are however many concerns, either because of teratogenicity (imatinib), immaturity of the foetal metabolizing pathways (tadalafil), or more generic lack of safety information (ONO-1301SR, BAY41-2272 & BAY60-2770). Treprostinil however does not have teratogenic effects in several animal studies, even when administered during embryogenesis, which is much earlier than the envisioned prenatal use for CDH.…”

Neonatal and fetal therapy of congenital diaphragmatic hernia-related pulmonary hypertension

“…Despite the benefits of FETO, one of its shortcomings remains the less than expected effect on pulmonary vascular development. Therefore, alternative prenatal, preferentially non-invasive treatment strategies that also address the pulmonary vascular development problem, reviewed elsewhere,55 need to be further developed. Theoretical solutions including pharmacological agents and stem cell therapy are possible, but any such strategy will meet the limitations of the placental barrier as well as the complexity of treating both the fetus as well as its mother.…”

“…There is early evidence that other drugs, including selexipag, imatinib, rosiglitazone, tadalafil, ONO-1301SR, BAY41-2272 and BAY60-2770, have the potential to improve PH features in different animal models of CDH. There are however many concerns, either because of teratogenicity (imatinib), immaturity of the fetal metabolising pathways (tadalafil) or more generic lack of safety information (ONO-1301SR, BAY41-2272 and BAY60-2770) 55…”

The heart in congenital diaphragmatic hernia: Knowns, unknowns, and future priorities

“…A variety of pre-natal pharmacotherapies aimed at modulating pulmonary vascular development have been investigated in pre-clinical CDH models (42). Sildenafil, a phosphodiesterase 5 inhibitor partially reverses pulmonary vascular abnormalities and lowering pulmonary vascular resistance and reducing RV hypertrophy in animal models (43)(44)(45).…”