RNAi modulation of placental sFLT1 for the treatment of preeclampsia

Turanov, Anton A.; Lo, Agnes S.; Hassler, Matthew R.; Makris, Angela; Ashar-Patel, Ami; Alterman, Julia F.; Coles, Andrew H.; Haraszti, Reka A.; Roux, Loïc; Godinho, Bruno M.D.C.; Echeverria, Dimas; Pears, Suzanne; Iliopoulos, Jim; Shanmugalingam, Renuka; Ogle, Robert; Zsengellér, Zsuzsanna K.; Hennessy, Annemarie; Karumanchi, S. Ananth; Moore, Melissa J.; Khvorova, Anastasia

doi:10.1038/nbt.4297

Cited by 151 publications

(108 citation statements)

References 71 publications

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“…RNA sequencing studies in human placentae from pre-eclamptic pregnancies suggest that three major isoforms of the FLT1 locus contribute to sFLT1 in the circulation 190 . In 2018, researchers identified novel RNAi molecules that specifically target all of the major sFLT1 mRNAs in cell culture studies 191 . They demonstrated that a single dose of sFLT1 RNAi therapy given intravenously lowered the sFLT1 protein level by 50%, which was accompanied by a reduction in blood pressure and proteinuria in a baboon model of pre-eclampsia.…”

Section: Rna Interference-based Strategiesmentioning

confidence: 99%

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

et al. 2019

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Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous preeclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

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Section: Rna Interference-based Strategiesmentioning

confidence: 99%

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

et al. 2019

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“…194 An alternative approach only tested in pre-clinical models is to knock down expression of sFlt in the placenta using interference RNA technology. 195 Other possible therapies are modifiers of endoplasmic reticulum stress, hydrogen sulphide donors, 161 and scavengers of fetal haemoglobin. 196…”

Section: Emerging Therapiesmentioning

confidence: 99%

Pre-eclampsia: pathophysiology and clinical implications

Burton

Redman

Roberts

et al. 2019

BMJ

790

696

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Pre-eclampsia is a common disorder that particularly affects first pregnancies. The clinical presentation is highly variable but hypertension and proteinuria are usually seen. These systemic signs arise from soluble factors released from the placenta as a result of a response to stress of syncytiotrophoblast. There are two sub-types: early and late onset pre-eclampsia, with others almost certainly yet to be identified. Early onset pre-eclampsia arises owing to defective placentation, whilst late onset pre-eclampsia may center around interactions between normal senescence of the placenta and a maternal genetic predisposition to cardiovascular and metabolic disease. The causes, placental and maternal, vary among individuals. Recent research has focused on placental-uterine interactions in early pregnancy. The aim now is to translate these findings into new ways to predict, prevent, and treat pre-eclampsia.

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“…Conjugation of oligonucleotides to a variety of chemical entities allows for modulation of bioavailability, tissues exposure and, in some cases, cell-type specific delivery ( 7–8 , 11 , 53 ). The recent approval of a fully chemically stabilized GalNAc siRNA, Givosiran, demonstrates the immense potential of conjugated siRNAs to treat genetic diseases ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy

Biscans

Caiazzi

Davis

et al. 2020

Nucleic Acids Research

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Small interfering RNAs (siRNAs) have revolutionized the treatment of liver diseases. However, robust siRNA delivery to other tissues represents a major technological need. Conjugating lipids (e.g. docosanoic acid, DCA) to siRNA supports extrahepatic delivery, but tissue accumulation and gene silencing efficacy are lower than that achieved in liver by clinical-stage compounds. The chemical structure of conjugated siRNA may significantly impact invivo efficacy, particularly in tissues with lower compound accumulation. Here, we report the first systematic evaluation of the impact of siRNA scaffold—i.e. structure, phosphorothioate (PS) content, linker composition—on DCA-conjugated siRNA delivery and efficacy in vivo. We found that structural asymmetry (e.g. 5- or 2-nt overhang) has no impact on accumulation, but is a principal factor for enhancing activity in extrahepatic tissues. Similarly, linker chemistry (cleavable versus stable) altered activity, but not accumulation. In contrast, increasing PS content enhanced accumulation of asymmetric compounds, but negatively impacted efficacy. Our findings suggest that siRNA tissue accumulation does not fully define efficacy, and that the impact of siRNA chemical structure on activity is driven by intracellular re-distribution and endosomal escape. Fine-tuning siRNA chemical structure for optimal extrahepatic efficacy is a critical next step for the progression of therapeutic RNAi applications beyond liver.

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RNAi modulation of placental sFLT1 for the treatment of preeclampsia

Cited by 151 publications

References 71 publications

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

Pre-eclampsia: pathophysiology and clinical implications

The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy

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