Emerging pharmacologic interventions for pre-eclampsia treatment

ABSTRACT

Introduction

Pre-eclampsia is a serious pregnancy complication and a major global concern for the mortality of both mother and fetus. Existing symptomatic treatments do not delay disease progression; thus, timely delivery of the baby is the most effective measure. However, the risk of various maternal and fetal injuries remains.

Areas covered

In this review, we summarize potential strategies for pharmacologic interventions in pre-eclamptic therapy. Specifically, we discuss the pathophysiological process of various effective candidate therapeutics that act on potential pathways and molecular targets to inhibit key stages of the disease. We refer to this pathogenesis-focused drug discovery model as a pathogenesis–target–drug (P–T–D) strategy. Finally, we discuss the introduction of nanotechnologies to improve the safety and efficacy of therapeutics via their specific placental targeting ability and placental retention effects.

Expert opinion

Despite the active development of novel pharmacological treatments based on our current knowledge of pre-eclamptic pathogenesis, investigations are still in the early phase. Thus, further exploration of the pathological mechanisms, integrated with the P–T–D strategy and novel nanosystems, could encourage more effective and safer strategies. Such advances could lead to a shift from expectant management to mechanistic-based therapy for pre-eclampsia.

KEYWORDS:

• Drug discovery
• mechanistic-based therapeutics
• molecular target
• nanotechnology
• pathogenesis
• pharmacology
• pre-eclampsia

Article highlights

• An improved understanding of pre-eclamptic pathogenesis has led to the emergence of novel preclinical and clinical therapeutic strategies to improve current clinical management.

• These emerging mechanistic-based therapeutics include small molecules, recombinant proteins, antibodies, and siRNA.

• Combination therapy based on a deeper understanding of pre-eclamptic etiology and pathogenesis is expected to achieve superior therapeutic effects in the treatment of pre-eclampsia.

• A primary concern in the development of pre-eclamptic drug treatments is the potential for off-target effects affecting both the mother and the fetus.

• In preclinical models, specific nanosystems are being developed to increase placental accumulation and reduce fetal exposure, with the aim of providing safe and efficient therapeutic delivery systems for pre-eclampsia.

This box summarizes key points contained in the article.

Abbreviations

FGR: fetal growth restriction; P–T–D: pathogenesis-targets-drugs; siRNA: short interfering RNA; sFlt-1: soluble fms-like tyrosine kinase-1; sEng: the soluble endoglin; TNF-α: tumor necrosis factor-α; CTB: cytotrophoblasts; STB: syncytiotrophoblasts; ECM: extracellular matrix; EVT: extra villous trophoblasts; iCTB: interstitial cytotrophoblasts; eCTB: endovascular cytotrophoblasts; IGFBP-1: Insulin-like growth factor binding protein-1; IGF: insulin-like growth factor; MMP: proteases matrix metalloproteinase; EGF: epidermal growth factor; HB-EGF: heparin-binding epidermal growth factor; ERBB: epidermal growth factor receptor; LMWH: low molecular weight heparin; EMT: epithelial-mesenchymal transition; HIFs: hypoxia inducible factors; TGF: transforming growth factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; Flt: fms-like tyrosine kinase; HSP27: heat-shock protein 27; RUPP: reduced uterine perfusion pressure; ROS: reactive oxygen species; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; SOD: superoxide dismutase; HO-1: hemoxygenase; GPx: glutathione peroxidase; TRX: thioredoxin; CoQ10: Coenzyme Q10; CO: carbon monoxide; Nrf-2: nuclear factor-erythroid-derived 2-related factor-2; PPIs: Proton pump inhibitors; H₂S: Hydrogen sulfide; CSE: cystathionine γ-lase; ATLs: aspirin-triggered lipoxins; LPS: lipopolysaccharide; PlGF: placental growth factor; phospho-eNOS: phosphorylated eNOS; L-NAME: L-nitro-arginine methyl ester; miRNA: microRNA; O₂: molecular oxygen; GSNO: S-Nitroso glutathione; Egr-1: early growth response protein-1; NK: natural killer; IL: Interleukin; NF-κB: nuclear factor kappa B; IL: Interleukin; C3: complement component 3; IVIg: Intravenous immunoglobulin; Ang II: angiotensin II; RAS: renin-angiotensin system; AT₁-AA: agonistic angiotensin II type 1 receptor autoantibody; AT₁R: angiotensin II type I receptor; ARB: AT1 receptor antagonist; ACEI: angiotensin-converting enzyme inhibitor; ET-1: Endothelin-1; ETA: endothelin A; COX-2: cyclooxygenase-2; HCQ: hydroxychloroquine; iRGD: internalizing Arg-Gly-Asp peptide; HbVs: hemoglobin vesicles; plCSA-BP: placental chondroitin sulfate A binding peptide; PAMAM: poly-amidoamine; ELP: elastin-like polypeptide.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2022.2134779

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are the founder and Executive Chairman of MirZyme Therapeutics Limited. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was financially supported by the National Natural Science Foundation of China (81873838) and Natural Science Foundation of Zhejiang Province (LYY21H300006).