Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1

Hariharan, Vignesh Narayan; Lo, Agnes S.; Turanov, Anton A.; Echeverria, Dimas; Sousa, Jacquelyn; McHugh, Nicholas; Biscans, Annabelle; Alterman, Julia F.; Karumanchi, S. Ananth; Moore, Melissa J.; Davis, Sarah M.

doi:10.1016/j.omtn.2022.06.009

Cited by 30 publications

(27 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A single dose was sufficient to mediate the silencing of sFlt‐1 and provide a therapeutic benefit 169 . This strategy has been further refined by introducing a chemical modification into the siRNA using a sequence‐specific duplex asymmetry and conjugation to phosphocholine‐docosanoic acid, 170 which increased placental accumulation, silencing efficiency and safety of sFlt‐1 targeting siRNAs 170 . Based on the available, the FDA has granted permission to test the safety of the siRNA approach in healthy humans (NCT05881993).…”

Section: Therapeutic Studiesmentioning

confidence: 99%

Translation of mechanistic advances in preeclampsia to the clinic: Long and winding road

Thadhani,

Cerdeira,

Karumanchi

2024

The FASEB Journal

Self Cite

View full text Add to dashboard Cite

As one of the leading causes of premature birth and maternal and infant mortality worldwide, preeclampsia remains a major unmet public health challenge. Preeclampsia and related hypertensive disorders of pregnancy are estimated to cause >75 000 maternal and 500 000 infant deaths globally each year. Because of rising rates of risk factors such as obesity, in vitro fertilization and advanced maternal age, the incidence of preeclampsia is going up with rates ranging from 5% to 10% of all pregnancies worldwide. A major discovery in the field was the realization that the clinical phenotypes related to preeclampsia, such as hypertension, proteinuria, and other adverse maternal/fetal events, are due to excess circulating soluble fms‐like tyrosine kinase‐1 (sFlt‐1, also referred to as sVEGFR‐1). sFlt‐1 is an endogenous anti‐angiogenic protein that is made by the placenta and acts by neutralizing the pro‐angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). During the last decade, this work has spawned a new era of molecular diagnostics for early detection of this condition. Antagonizing sFlt‐1 either by reducing production or blocking its actions has shown salutary effects in animal models. Further, in early‐stage human studies, the therapeutic removal of sFlt‐1 from maternal circulation has shown promise in delaying disease progression and improving outcomes. Recently, the FDA approved the first molecular test for preterm preeclampsia (sFlt‐1/PlGF ratio) for clinical use in the United States. Measuring serum sFlt‐1/PlGF ratio in the acute hospital setting may aid short‐term management, particularly regarding step‐up or step‐down of care, decision to transfer to settings better equipped to manage both the mother and the preterm neonate, appropriate timing of administration of steroids and magnesium sulfate, and in expectant management decisions. The test itself has the potential to save lives. Furthermore, the availability of a molecular test that correlates with adverse outcomes has set the stage for interventional clinical trials testing treatments for this disorder. In this review, we will discuss the role of circulating sFlt‐1 and related factors in the pathogenesis of preeclampsia and specifically how this discovery is leading to concrete advances in the care of women with preeclampsia.

show abstract

Section: Therapeutic Studiesmentioning

confidence: 99%

Translation of mechanistic advances in preeclampsia to the clinic: Long and winding road

Thadhani,

Cerdeira,

Karumanchi

2024

The FASEB Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…5,56 In the future, the sFlt-1/PlGF ratio may also help identify patients with angiogenic imbalance who are most likely to benefit from putative therapies for preeclampsia such as complement inhibition, 57,58 recombinant PlGF, 59,60 apheresis to remove sFlt-1 from circulation, 61,62 or short interfering RNAs that silence sFlt-1 mRNA production. 63,64 The angiogenic biomarker PlGF is already being used in the first trimester, in conjunction with other laboratory measures and clinical features, to predict preeclampsia, 65 and such efforts have helped identify those patients most likely to benefit Fig. 1.…”

Section: Use Of the Soluble Fms-like Tyrosine Kinase-1/placental Grow...mentioning

confidence: 99%

“…In the future, the sFlt-1/PlGF ratio may also help identify patients with angiogenic imbalance who are most likely to benefit from putative therapies for preeclampsia such as complement inhibition, 57,58 recombinant PlGF, 59,60 apheresis to remove sFlt-1 from circulation, 61,62 or short interfering RNAs that silence sFlt-1 mRNA production. 63,64 The angiogenic biomarker PlGF is already being used in the first trimester, in conjunction with other laboratory measures and clinical features, to predict preeclampsia, 65 and such efforts have helped identify those patients most likely to benefit from low-dose aspirin to prevent disease. 66 Additional work will be needed to determine how angiogenic biomarkers can be used in conjunction with remote monitoring devices and machine learning techniques to further identify high-risk patients and to decrease preeclampsia-related adverse outcomes.…”

Section: Use Of the Soluble Fms-like Tyrosine Kinase-1/placental Grow...mentioning

confidence: 99%

Angiogenic Biomarkers in Preeclampsia

Burwick,

Rodriguez

2024

Obstetrics &Amp; Gynecology

View full text Add to dashboard Cite

Preeclampsia contributes disproportionately to maternal and neonatal morbidity and mortality throughout the world. A critical driver of preeclampsia is angiogenic imbalance, which is often present weeks to months before overt disease. Two placenta-derived angiogenic biomarkers, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), have proved useful as diagnostic and prognostic tests for preeclampsia. Recently, the U.S. Food and Drug Administration approved the sFlt-1/PlGF assay to aid in the prediction of preeclampsia with severe features among women with hypertensive disorders of pregnancy at 24–34 weeks of gestation. In this narrative review, we summarize the body of work leading to this approval and describe how the sFlt-1/PlGF ratio may be implemented in clinical practice as an adjunctive measure to help optimize care and to reduce adverse outcomes in preeclampsia.

show abstract

“…Turanov et al [124,125 ▪▪ ] developed a short interference RNA (siRNA) strategy to silence placental sFlt-1. Of note, this is targeted to specific isoforms and does not interfere with the full length receptor Flt-1.…”

Section: Novel Diagnostic Approachesmentioning

confidence: 99%

Novel therapeutic and diagnostic approaches for preeclampsia

Vatish

Powys

Cerdeira

2023

Current Opinion in Nephrology &Amp; Hypertension

View full text Add to dashboard Cite

Purpose of reviewThis review will summarize recent findings relating to the diagnostic approach to preeclampsia and current avenues of research aimed at modifying the underlying disease process. Recent findingsGrowing international consensus supports a broad preeclampsia definition that incorporates maternal endorgan and uteroplacental dysfunction. Recent evidence demonstrates that this definition better identifies women and babies at risk of adverse outcomes compared to the traditional definition of hypertension and proteinuria. Multiple studies have demonstrated the usefulness and cost-effectiveness of angiogenic biomarkers such as soluble fms-like tyrosine kinase-1 and placental growth factor as a clinical adjunct to diagnose and predict severity of preeclampsia associated outcomes. Current novel therapeutic approaches to preeclampsia target pathogenic pathways (e.g. antiangiogenesis) or downstream effects such as oxidative stress and nitric oxide. Recent findings relating to these promising candidates are discussed. Multicenter clinical trials are needed to evaluate their effectiveness and ability to improve fetal and maternal outcomes.

show abstract

Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1

Cited by 30 publications

References 81 publications

Translation of mechanistic advances in preeclampsia to the clinic: Long and winding road

Translation of mechanistic advances in preeclampsia to the clinic: Long and winding road

Angiogenic Biomarkers in Preeclampsia

Novel therapeutic and diagnostic approaches for preeclampsia

Contact Info

Product

Resources

About