RARE DISEASE
Placental insufficiency
Placental insufficiency
Placental insufficiency
Synonyms: Uteroplacental vascular insufficiency
Synonyms: Uteroplacental vascular insufficiency
Synonyms: Uteroplacental vascular insufficiency
Drug discovery
1
drug
With orphan designation
Overview
Placental insufficiency is a progressive deterioration in placental function, impairing oxygen/nutrient transfer to the fetus, often linked to preeclampsia, intrauterine growth restriction (IUGR), and preterm birth [1][3][13]. It is a leading contributor to perinatal morbidity and mortality, with complications including stillbirth, hypoxic-ischemic encephalopathy, and long-term neurodevelopmental/cardiometabolic risks [1][9][17]. Diagnosis relies on Doppler ultrasonography, fetal biometry, and clinical monitoring [6][9].
Categories: rare gynecological and obstetric diseases
Research Papers
1,027 drug discovery papers about Placental insufficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,027 drug discovery papers about Placental insufficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-11 | Complement as a driver of immune-vascular heterogeneity across preeclampsia subtypes: toward a precision medicine framework.
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity worldwide, traditionally defined as a hypertensive disorder of pregnancy but increasingly recognized as a heterogeneous syndrome with diverse biological origins. Emerging evidence indicates that distinct pathogenic pathways-including placental insufficiency, maternal cardiometabolic dysfunction, and intrinsic immune dysregulation-contribute to different clinical phenotypes of the disease. Among these, the complement system has gained attention as a central regulator of immune-vascular interactions during pregnancy. Recent studies demonstrate that tightly controlled complement activation is required for normal placental development, whereas dysregulation of this system contributes to endothelial injury, inflammation, and microvascular dysfunction characteristic of PE. Importantly, complement activation patterns differ across disease subtypes: classical pathway activation predominates in placental-driven early-onset PE, chronic low-grade alternative pathway activation is associated with maternal metabolic disease, and genetic or functional defects in complement regulation define a subset of severe, complement-mediated cases with overlap features of thrombotic microangiopathy. Despite these advances, current diagnostic and therapeutic approaches remain largely non-specific and fail to account for this biological heterogeneity. Here, we propose a subtype-based framework of PE centered on complement dysregulation, integrating mechanistic, genetic, and clinical evidence. This model links distinct complement activation patterns to disease trajectories and identifies corresponding biomarker signatures and therapeutic targets. By redefining PE as a spectrum of complement-stratified disorders, this Review provides a conceptual foundation for precision diagnostics and mechanism-guided therapy. Such an approach has the potential to improve risk stratification, enable earlier detection, and support the development of targeted interventions tailored to individual disease mechanisms.
2026-06-29 | Vaginal microbiota in the first trimester of pregnancy and the development of placental insufficiency
Fetal growth restriction and preeclampsia, the underlying pathogenesis of which is placental insufficiency, are among the leading causes of perinatal and maternal morbidity and mortality worldwide. Objective. To study the association between vaginal microbiome and placental protein levels in the first trimester of pregnancy with the risk of developing of placental insufficiency. Material and methods. The study included 283 patients without history of obstetrical, gynecologic, or medical conditions. Each patient had their placental protein levels assessed-human chorionic gonadotropin (hCG) and placental-associated plasma protein A (PAPP-A) — based on the initial screening, and their vaginal microbiota in the first trimester of pregnancy was analyzed using polymerase chain reaction. Depending on whether placental insufficiency subsequently developed, all patients were divided into two groups: Group 1 — 203 patients without placental insufficiency; Group 2 — 80 patients whose pregnancy was complicated by the development of placental insufficiency. Results. Patients of Group 2 had statistically significant lower concentrations of placental proteins — hCG and PAPP-A — as well as higher levels of Gardnerella vaginalis, Prevotella bivia, Porphyromonas spp., and Eubacterium spp. — were detected in the first trimester of pregnancy compared to those in Group 1. According to the study results, with a PAPP-A MoM level ≤0.486 based on the first prenatal screening data and the number of Sneathia spp., Leptotrichia spp., and Fusobacterium spp. bacteria, A vaginal microbiota with ≤107.3 DNA copies is associated with a high risk of developing placental insufficiency. Conclusion. Patients with reduced levels of placental proteins based on the initial prenatal screening and higher numbers of opportunistic microorganisms in the first trimester of pregnancy have a higher risk of developing placental insufficiency in late gestation. Timely correction of the vaginal microbiota during the preconception period and early pregnancy may be an important way to prevent placental insufficiency.
2026-06-25 | USP22 suppresses trophoblast cell necroptosis in preeclampsia by stabilizing KAT2A-mediated histone acetylation at the SFRP1 promoter.
Preeclampsia (PE) is a severe gestational disorder associated with impaired placental function. Necroptosis contributes substantially to trophoblast injury in PE, though the upstream epigenetic regulatory pathways are not yet fully elucidated. This study investigated how the deubiquitinase USP22 suppresses trophoblast necroptosis via epigenetic modulation of the KAT2A-SFRP1 axis. Preeclamptic and normal placental tissues were analyzed for USP22 and necroptosis pathway components by immunohistochemistry. Hypoxic conditions established in HTR-8/SVneo trophoblasts simulated the preeclamptic microenvironment. Cell death modality was characterized through complementary approaches including flow cytometry, cell viability assays, and transmission electron microscopy. Pathway selectivity was determined through systematic pharmacological inhibition of necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagy. RNA sequencing identified genome-wide transcriptional responses to USP22 perturbation. Direct protein-protein interactions and locus-specific histone modifications at the SFRP1 promoter were resolved by co-immunoprecipitation and chromatin immunoprecipitation followed by quantitative PCR. USP22-mediated deubiquitination of KAT2A and substrate ubiquitin chain linkage specificity were elucidated using protein stability assays, ubiquitination analysis, and catalytic activity-dependent rescue with a C185A point mutant. Findings were further validated in an in vivo L-NAME-induced rat model of PE. USP22 was significantly downregulated in PE placental tissues, concomitant with elevated expression of RIPK1, RIPK3, and MLKL. Necroptosis was confirmed as the dominant death modality in hypoxic trophoblasts. USP22 knockdown exacerbated necroptotic signaling, while USP22 overexpression restored H3K9ac and H3K27ac levels and suppressed necroptosis. RNA sequencing analysis identified 1,186 differentially expressed genes following USP22 knockdown, including notably repressed expression of the Wnt antagonist SFRP1. Mechanistically, USP22 directly interacted with KAT2A and stabilized it by selectively cleaving K48-linked polyubiquitin chains. This stabilization sustained KAT2A-dependent histone acetylation at the SFRP1 promoter, thereby maintaining SFRP1 transcription. Importantly, SFRP1 restoration in USP22-deficient trophoblasts substantially mitigated cell death and decreased the p-MLKL/MLKL ratio. The L-NAME rat PE model further confirmed coordinated downregulation of USP22, KAT2A, SFRP1, and histone acetylation marks in vivo. USP22 maintains trophoblast survival through selective K48-deubiquitination of KAT2A, which stabilizes KAT2A and sustains histone acetylation at the SFRP1 promoter, thereby promoting SFRP1 transcription and suppressing RIPK1-RIPK3-MLKL-mediated necroptosis. The USP22-KAT2A-SFRP1 axis represents a novel epigenetic checkpoint in PE pathogenesis and a potential therapeutic target for placental insufficiency.
2026-07-11 | Complement as a driver of immune-vascular heterogeneity across preeclampsia subtypes: toward a precision medicine framework.
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity worldwide, traditionally defined as a hypertensive disorder of pregnancy but increasingly recognized as a heterogeneous syndrome with diverse biological origins. Emerging evidence indicates that distinct pathogenic pathways-including placental insufficiency, maternal cardiometabolic dysfunction, and intrinsic immune dysregulation-contribute to different clinical phenotypes of the disease. Among these, the complement system has gained attention as a central regulator of immune-vascular interactions during pregnancy. Recent studies demonstrate that tightly controlled complement activation is required for normal placental development, whereas dysregulation of this system contributes to endothelial injury, inflammation, and microvascular dysfunction characteristic of PE. Importantly, complement activation patterns differ across disease subtypes: classical pathway activation predominates in placental-driven early-onset PE, chronic low-grade alternative pathway activation is associated with maternal metabolic disease, and genetic or functional defects in complement regulation define a subset of severe, complement-mediated cases with overlap features of thrombotic microangiopathy. Despite these advances, current diagnostic and therapeutic approaches remain largely non-specific and fail to account for this biological heterogeneity. Here, we propose a subtype-based framework of PE centered on complement dysregulation, integrating mechanistic, genetic, and clinical evidence. This model links distinct complement activation patterns to disease trajectories and identifies corresponding biomarker signatures and therapeutic targets. By redefining PE as a spectrum of complement-stratified disorders, this Review provides a conceptual foundation for precision diagnostics and mechanism-guided therapy. Such an approach has the potential to improve risk stratification, enable earlier detection, and support the development of targeted interventions tailored to individual disease mechanisms.
2026-06-29 | Vaginal microbiota in the first trimester of pregnancy and the development of placental insufficiency
Fetal growth restriction and preeclampsia, the underlying pathogenesis of which is placental insufficiency, are among the leading causes of perinatal and maternal morbidity and mortality worldwide. Objective. To study the association between vaginal microbiome and placental protein levels in the first trimester of pregnancy with the risk of developing of placental insufficiency. Material and methods. The study included 283 patients without history of obstetrical, gynecologic, or medical conditions. Each patient had their placental protein levels assessed-human chorionic gonadotropin (hCG) and placental-associated plasma protein A (PAPP-A) — based on the initial screening, and their vaginal microbiota in the first trimester of pregnancy was analyzed using polymerase chain reaction. Depending on whether placental insufficiency subsequently developed, all patients were divided into two groups: Group 1 — 203 patients without placental insufficiency; Group 2 — 80 patients whose pregnancy was complicated by the development of placental insufficiency. Results. Patients of Group 2 had statistically significant lower concentrations of placental proteins — hCG and PAPP-A — as well as higher levels of Gardnerella vaginalis, Prevotella bivia, Porphyromonas spp., and Eubacterium spp. — were detected in the first trimester of pregnancy compared to those in Group 1. According to the study results, with a PAPP-A MoM level ≤0.486 based on the first prenatal screening data and the number of Sneathia spp., Leptotrichia spp., and Fusobacterium spp. bacteria, A vaginal microbiota with ≤107.3 DNA copies is associated with a high risk of developing placental insufficiency. Conclusion. Patients with reduced levels of placental proteins based on the initial prenatal screening and higher numbers of opportunistic microorganisms in the first trimester of pregnancy have a higher risk of developing placental insufficiency in late gestation. Timely correction of the vaginal microbiota during the preconception period and early pregnancy may be an important way to prevent placental insufficiency.
2026-06-25 | USP22 suppresses trophoblast cell necroptosis in preeclampsia by stabilizing KAT2A-mediated histone acetylation at the SFRP1 promoter.
Preeclampsia (PE) is a severe gestational disorder associated with impaired placental function. Necroptosis contributes substantially to trophoblast injury in PE, though the upstream epigenetic regulatory pathways are not yet fully elucidated. This study investigated how the deubiquitinase USP22 suppresses trophoblast necroptosis via epigenetic modulation of the KAT2A-SFRP1 axis. Preeclamptic and normal placental tissues were analyzed for USP22 and necroptosis pathway components by immunohistochemistry. Hypoxic conditions established in HTR-8/SVneo trophoblasts simulated the preeclamptic microenvironment. Cell death modality was characterized through complementary approaches including flow cytometry, cell viability assays, and transmission electron microscopy. Pathway selectivity was determined through systematic pharmacological inhibition of necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagy. RNA sequencing identified genome-wide transcriptional responses to USP22 perturbation. Direct protein-protein interactions and locus-specific histone modifications at the SFRP1 promoter were resolved by co-immunoprecipitation and chromatin immunoprecipitation followed by quantitative PCR. USP22-mediated deubiquitination of KAT2A and substrate ubiquitin chain linkage specificity were elucidated using protein stability assays, ubiquitination analysis, and catalytic activity-dependent rescue with a C185A point mutant. Findings were further validated in an in vivo L-NAME-induced rat model of PE. USP22 was significantly downregulated in PE placental tissues, concomitant with elevated expression of RIPK1, RIPK3, and MLKL. Necroptosis was confirmed as the dominant death modality in hypoxic trophoblasts. USP22 knockdown exacerbated necroptotic signaling, while USP22 overexpression restored H3K9ac and H3K27ac levels and suppressed necroptosis. RNA sequencing analysis identified 1,186 differentially expressed genes following USP22 knockdown, including notably repressed expression of the Wnt antagonist SFRP1. Mechanistically, USP22 directly interacted with KAT2A and stabilized it by selectively cleaving K48-linked polyubiquitin chains. This stabilization sustained KAT2A-dependent histone acetylation at the SFRP1 promoter, thereby maintaining SFRP1 transcription. Importantly, SFRP1 restoration in USP22-deficient trophoblasts substantially mitigated cell death and decreased the p-MLKL/MLKL ratio. The L-NAME rat PE model further confirmed coordinated downregulation of USP22, KAT2A, SFRP1, and histone acetylation marks in vivo. USP22 maintains trophoblast survival through selective K48-deubiquitination of KAT2A, which stabilizes KAT2A and sustains histone acetylation at the SFRP1 promoter, thereby promoting SFRP1 transcription and suppressing RIPK1-RIPK3-MLKL-mediated necroptosis. The USP22-KAT2A-SFRP1 axis represents a novel epigenetic checkpoint in PE pathogenesis and a potential therapeutic target for placental insufficiency.
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Drug Discovery Landscape
1 orphan drug designation for Placental insufficiency.
1 orphan drug designation for Placental insufficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adenoviral vector serotype 5 containing the vascular endothelial growth factor D isoform (preprocessed short form) from a CMV promoter | gene therapies | EMA | 2015-01-15 | — | Magnus Invention Management Ltd |
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