RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A

Lin, Wenyi; Zhu, Ruiqi; Zhang, Zhen; Lu, Xuan; Wang, Huafang; Wang, He; Hu, Yu; Tang, Liang

doi:10.1016/j.omtn.2021.03.022

Cited by 5 publications

(3 citation statements)

References 56 publications

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“…Additionally, future studies will involve modifying these nanoparticles to knockdown therapeutic targets in other cancer types, as well as other disease indications. We envision this work can directly benefit siRNA therapies in current clinical development that target clotting factors to treat thrombosis and hemophilia, as these targets are directly upstream of the protease thrombin ( 51 , 52 ). We have performed extensive work to explore the rich protease biology underpinning a number of diseases such as lung pathologies ( 53 – 55 ), pneumonia ( 56 ), and bacterial infection ( 57 ), which could be leveraged to enhance RNAi delivery in these indications.…”

Section: Discussionmentioning

confidence: 99%

Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system

Hao,

Boehnke,

Elledge

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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RNA interference (RNAi) therapeutics are an emerging class of medicines that selectively target mRNA transcripts to silence protein production and combat disease. Despite the recent progress, a generalizable approach for monitoring the efficacy of RNAi therapeutics without invasive biopsy remains a challenge. Here, we describe the development of a self-reporting, theranostic nanoparticle that delivers siRNA to silence a protein that drives cancer progression while also monitoring the functional activity of its downstream targets. Our therapeutic target is the transcription factor SMARCE1, which was previously identified as a key driver of invasion in early-stage breast cancer. Using a doxycycline-inducible shRNA knockdown in OVCAR8 ovarian cancer cells both in vitro and in vivo, we demonstrate that SMARCE1 is a master regulator of genes encoding proinvasive proteases in a model of human ovarian cancer. We additionally map the peptide cleavage profiles of SMARCE1-regulated proteases so as to design a readout for downstream enzymatic activity. To demonstrate the therapeutic and diagnostic potential of our approach, we engineered self-assembled layer-by-layer nanoparticles that can encapsulate nucleic acid cargo and be decorated with peptide substrates that release a urinary reporter upon exposure to SMARCE1-related proteases. In an orthotopic ovarian cancer xenograft model, theranostic nanoparticles were able to knockdown SMARCE1 which was in turn reported through a reduction in protease-activated urinary reporters. These LBL nanoparticles both silence gene products by delivering siRNA and noninvasively report on downstream target activity by delivering synthetic biomarkers to sites of disease, enabling dose-finding studies as well as longitudinal assessments of efficacy.

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Section: Discussionmentioning

confidence: 99%

Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system

Hao,

Boehnke,

Elledge

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“… 68 The effect of RNAi on HCII has been studied in mice by conjugating siRNA-HCII with Ga1NAc. 69 This study suggested that by inhibition of HCII thrombin generation could be upregulated and hemostatic ability improved thus making HCII a potential target for hemophilia treatment.…”

Section: Other Strategies For Rnai Therapeutics In Hemophiliamentioning

confidence: 96%

RNAi for the Treatment of People with Hemophilia: Current Evidence and Patient Selection

Boyce¹,

Rangarajan²

2023

JBM

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Severe hemophilia is associated with spontaneous, prolonged and recurrent bleeding. Inadequate prevention and treatment of bleeding can lead to serious morbidity and mortality. Due to the limitations of intravenous clotting factor replacement, including the risk of inhibitory antibodies, innovative novel therapies have been developed that have dramatically changed the landscape of hemophilia therapy. Ribonucleic acid interference (RNAi) has brought the opportunity for multiple strategies to manipulate the hemostatic system and ameliorate the bleeding phenotype in severe bleeding disorders. Fitusiran is a RNAi therapeutic that inhibits the expression of the natural anticoagulant serpin antithrombin. Reduction in antithrombin is known to cause thrombosis if coagulation parameters are otherwise normal and can rebalance hemostasis in severe hemophilia. Reports from late stage clinical trials of fitusiran in hemophilia A and B participants, with and without inhibitory antibodies to exogenous clotting factor, have demonstrated efficacy in preventing bleeding events showing promise for a future “universal” prophylactic treatment of individuals with moderate-severe hemophilia.

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“…Because of individual variances in FVIII activity, the typical dose regimen of recombinant FVIII must be further formed to ensure the regulation of supplemental proteins in plasma for efficiently minimizing bleeding. However, in a recent study, asialoglycoprotein receptor ligand ( N -acetylgalactosamine [GalNAc]-heparin cofactor II [HCII]) was conjugated to small interfering RNA, allowing for active targeting to the liver targeting the heparin cofactor II [ 52 ].…”

Section: Targeting Strategies For Achieving Hemostasismentioning

confidence: 99%

Recent advances in biopolymer-based hemostatic materials

Mecwan

Falcone

et al. 2022

Regenerative Biomaterials

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Hemorrhage is the leading cause of trauma-related deaths, in hospital and pre-hospital settings. Hemostasis is a complex mechanism that involves a cascade of clotting factors and proteins that result in the formation of a strong clot. In certain surgical and emergency situations, hemostatic agents are needed to achieve faster blood coagulation to prevent the patient from experiencing a severe hemorrhagic shock. Therefore, it is critical to consider appropriate materials and designs for hemostatic agents. Many materials have been fabricated as hemostatic agents, including synthetic and naturally derived polymers. However, compared to synthetic polymers, natural polymers or biopolymers, which include polysaccharides and polypeptides, have greater biocompatibility, biodegradability, and processibility. Thus, in this review, we focus on biopolymer-based hemostatic agents of different forms, such as powder, particles, sponges, and hydrogels. Finally, we discuss biopolymer-based hemostats currently in clinical trials and offer insight into next-generation hemostats for clinical translation.

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RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A

Cited by 5 publications

References 56 publications

Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system

Targeting and monitoring ovarian cancer invasion with an RNAi and peptide delivery system

RNAi for the Treatment of People with Hemophilia: Current Evidence and Patient Selection

Recent advances in biopolymer-based hemostatic materials

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