Review
Pharmacology & Pharmacy
Lei Zhang, Yayu Liang, Guohui Liang, Zhili Tian, Yue Zhang, Zhihui Liu, Xinying Ji
Summary: This article introduces RNA interference technology and its application in genetic therapy, focusing on the advantages and limitations of GalNAc-siRNA conjugates and lipid nanoparticles as delivery systems, and looking forward to the development of oligonucleotide drugs in genetic therapy.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Oluwakemi Ebenezer, Pietro Comoglio, Gane Ka-Shu Wong, Jack A. Tuszynski
Summary: In the past two decades, the introduction of synthetic siRNAs into the cytoplasm has been found to effectively silence targeted genes, impacting gene expression and regulation. Extensive investments have been made in developing RNA therapeutics, including for diseases related to PCSK9. PCSK9 plays a crucial role in LDL-C uptake, and loss-of-function modifications of PCSK9 have shown significant clinical importance in reducing cholesterol levels and lowering the risk of CVD. Monoclonal antibodies and siRNA drugs targeting PCSK9 offer a promising option for managing lipid disorders and improving CVD outcomes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Saket Agarwal, Ruth Allard, Justin Darcy, Samantha Chigas, Yongli Gu, Tuyen Nguyen, Sarah Bond, Saeho Chong, Jing-Tao Wu, Maja M. Janas
Summary: The study evaluated the impact of serum proteins on the uptake and activity of GalNAc-conjugated siRNAs in primary human hepatocytes, finding that although a significant portion of the GalNAc-conjugated siRNAs is bound to serum proteins, the presence of serum had minimal impact on the ASGPR-mediated uptake and activity of GalNAc-conjugated siRNAs compared to their uptake and activity in the absence of serum.
NUCLEIC ACID THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Sudong Kong, Xiaoqing Gao, Qianhui Wang, Jianguo Lin, Ling Qiu, Minhao Xie
Summary: A novel dithiomaleimides-based tetra-antennary GalNAc conjugate was successfully developed for efficient siRNA delivery and good traceability. It can be easily constructed through three click-type reactions and has comparable siRNA delivery efficiency to the GalNAc L96 standard. In addition, the internal DTMs provide highly fluorescent emission, benefiting delivery tracking and reducing the cost and side effects of extra addition of hydrophobic dye molecules.
Article
Chemistry, Multidisciplinary
Francesca Perrone, Emanuela Fabiola Craparo, Maja Cemazar, Urska Kamensek, Salvatore Emanuele Drago, Barbara Dapas, Bruna Scaggiante, Fabrizio Zanconati, Debora Bonazza, Mario Grassi, Nhung Truong, Gabriele Pozzato, Rossella Farra, Gennara Cavallaro, Gabriele Grassi
Summary: The study demonstrates the valuable potential of PDPG for specific delivery of siRNAs targeting HCC-related genes, leading to reduced HCC cell vitality and downregulation of target gene expression.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Medicine, Research & Experimental
Yufei Pan, Jing Guan, Yujing Gao, Yuejie Zhu, Huantong Li, Hua Guo, Qianyi He, Zhu Guan, Zhenjun Yang
Summary: ASO is a therapeutic targeting mRNA or genes, and its effective delivery and accumulation in target tissues in vivo remain challenging. Liposome-delivered ASOs with increased hepatic accumulation were explored, and structurally optimized CT102 showed potential for the treatment of hepatocellular carcinoma.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Chemistry, Medicinal
Mian Wang, Zhenjie Li, Feiyang Liu, Qingyuan Yi, Chunxiao Pu, Yajie Li, Tingrong Luo, Jian Liang, Jianyi Wang
Summary: The antitumor beta-elemene derivative W-105 and three novel hepatocyte-targeting prodrugs (W-1-5, W-2-9, and W-3-8) show promising potential in liver cancer treatment due to their excellent antitumor activity, low toxic side effects, and specific targeting abilities.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Jiajia Wang, Wei Zhang, Wei Cao, Kang Liu, Shihao Su, Jing Ma, Xia Li
Summary: This study develops a simple strategy to synthesize various GalNAc glycosides using rare earth metal triflates. The results demonstrate that both alpha-glycosides and beta-glycosides of GalNAc can be obtained by conducting with Hf(OTf)(4) and Sc(OTf)(3) respectively. This strategy can be used to prepare various GalNAc-containing substrates.
FRONTIERS IN CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Adrianna Dec, Aleksandra Niemiec, Eliza Wojciechowska, Mateusz Maliglowka, Lukasz Buldak, Aleksandra Boldys, Boguslaw Okopien
Summary: Hypercholesterolemia is an undertreated and underdiagnosed disease that plays a crucial role in atherosclerosis development. In recent years, novel lipid-lowering therapies such as inclisiran, a small interfering RNA (siRNA), have been introduced to address this issue. Inclisiran increases the number of LDL receptors on hepatic cells, potentially lowering plasma LDL cholesterol level and showing promising efficacy for future hypolipemic therapies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Chunyan Yang, Zixuan Guan, Xincheng Pang, Zengqi Tan, Xiaomin Yang, Xiang Li, Feng Guan
Summary: A delivery system based on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) loaded with doxorubicin (Dox) was developed for potential therapy of hepatocellular carcinoma (HCC). The desialylated MSC-EVs exhibited improved cellular uptake and targeting efficacy in vitro and in vivo.
Article
Engineering, Biomedical
Nathan Schiffmann, Yifei Liang, Carlos E. Nemcovsky, Michal Almogy, Michal Halperin-Sternfeld, Nathan C. Gianneschi, Lihi Adler-Abramovich, Eyal Rosen
Summary: Diabetes is a global epidemic that affects wound healing and increases the risk of infections. This study presents the use of enzyme-responsive nanoparticles to specifically deliver an anti-inflammatory drug, dexamethasone, to treat inflammation in diabetes. The nanoparticles show prolonged accumulation in inflamed tissue, leading to improved therapeutic efficacy in reducing inflammation. These results demonstrate the potential of enzyme-responsive nanoparticles as targeted delivery vehicles for the treatment of diabetic and other inflammatory wounds.
ADVANCED HEALTHCARE MATERIALS
(2023)
Review
Medicine, General & Internal
Sylwester Rogula, Ewelina Blazejowska, Aleksandra Gasecka, Lukasz Szarpak, Milosz J. Jaguszewski, Tomasz Mazurek, Krzysztof J. Filipiak
Summary: Lowering circulating low-density lipoprotein-cholesterol (LDL-C) is crucial for reducing cardiovascular risk, but existing therapies may not be effective for all patients. Inclisiran, a novel small interfering RNA (siRNA)-based therapeutic, shows promise in significantly reducing LDL-C levels with a simple dosing regimen. Further research is needed to explore its potential benefits in managing dyslipidemia and improving cardiovascular outcomes.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Pharmacology & Pharmacy
Yanzhen Zhang, Huaigang Chen, Lang Hong, Hong Wang, Bin Li, Mengyin Zhang, Jiamei Li, Liu Yang, Fan Liu
Summary: This review summarizes the mechanism, efficacy, safety, and applications of Inclisiran, a novel siRNA drug that targets PCSK9 gene expression to reduce LDL-C levels. It compares Inclisiran with other lipid-lowering drugs, highlighting its convenience and effectiveness for high cardiovascular risk patients. However, further research is needed to investigate its long-term safety and efficacy, cost-effectiveness and accessibility, and interactions with other drugs.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Applied
Prince Allawadhi, Vishakha Singh, Kannan Govindaraj, Isha Khurana, Lopmudra P. Sarode, Umashanker Navik, Anil Kumar Banothu, Ralf Weiskirchen, Kala Kumar Bharani, Amit Khurana
Summary: Polysaccharides are important biological polymers with diverse applications. Polysaccharide nanoparticles exhibit excellent drug delivery properties and therapeutic effects, making them promising for applications in diabetes, organ fibrosis, and arthritis.
CARBOHYDRATE POLYMERS
(2022)
Review
Pharmacology & Pharmacy
Lukasz Wolowiec, Joanna Osiak, Anna Wolowiec, Aleksandra Wijata, Elzbieta Grzesk, Mariusz Kozakiewicz, Joanna Banach, Alicja Nowaczyk, Jacek Nowaczyk, Grzegorz Grzesk
Summary: Dyslipidemia is an important risk factor for cardiovascular disease. Statins have been the basis of lipid-lowering therapy, but their efficacy is often limited. The discovery of PCSK9 protein has led to the development of new protein-based drugs, including antibody drugs and siRNA drugs. This article aims to summarize the molecular mechanisms, pharmacokinetics, and pharmacodynamics of the siRNA drug inclisiran, and review the latest research.
Article
Medicine, General & Internal
Brian A. Ference, Deepak L. Bhatt, Alberico L. Catapano, Chris J. Packard, Ian Graham, Stephen Kaptoge, Thatcher B. Ference, Qi Guo, Ulrich Laufs, Christian T. Ruff, Arjen Cupido, G. Kees Hovingh, John Danesh, Michael V. Holmes, George Davey Smith, Kausik K. Ray, Stephen J. Nicholls, Marc S. Sabatine
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
(2019)
Article
Cardiac & Cardiovascular Systems
Lotte C. A. Stiekema, Koen H. M. Prange, Renate M. Hoogeveen, Simone L. Verweij, Jeffrey Kroon, Johan G. Schnitzler, Kim E. Dzobo, Arjen J. Cupido, Sotirios Tsimikas, Erik S. G. Stroes, Menno P. J. de Winther, Mahnoush Bahjat
EUROPEAN HEART JOURNAL
(2020)
Article
Cardiac & Cardiovascular Systems
Lubna Ali, Arjen J. Cupido, Maaike Rijkers, G. Kees Hovingh, Adriaan G. Holleboom, Geesje M. Dallinga-Thie, Erik S. G. Stroes, Marjolein A. W. van den Boogert
Review
Biochemistry & Molecular Biology
Arjen J. Cupido, Tycho R. Tromp, G. Kees Hovingh
Summary: Polygenic risk scores (PRS) for LDL cholesterol (LDL-C) have potential clinical relevance and may serve as sensitive tools for identifying individuals with increased cardiovascular disease (CVD) risk. PRS can help explain part of hypercholesterolemia in patients without monogenic FH and modulate CVD risk even in individuals without monogenic FH. However, current LDL-C PRS do not match the cardiovascular risk conferred by monogenic FH, and they are not widely used in clinical care.
CURRENT OPINION IN LIPIDOLOGY
(2021)
Article
Cardiac & Cardiovascular Systems
Tycho R. Tromp, Arjen J. Cupido, Laurens F. Reeskamp, Erik S. G. Stroes, G. Kees Hovingh, Joep C. Defesche, Amand F. Schmidt, Linda Zuurbier
Summary: LDL-C levels vary in patients with familial hypercholesterolemia (FH). This study found that a polygenic score (PS) comprising 12 genetic variants was higher in FH patients and associated with incident coronary artery disease (CAD). However, adding the PS to readily available characteristics did not improve the accuracy of CAD risk prediction, suggesting limited discriminative value for CAD.
Article
Pharmacology & Pharmacy
Arjen J. Cupido, Folkert W. Asselbergs, Pradeep Natarajan, Paul M. Ridker, G. Kees Hovingh, A. Floriaan Schmidt
Summary: Targeting IL-6 and IL-6 receptor can reduce the risk of multiple cardiometabolic diseases, suggesting both IL-6 and IL-6R are potential therapeutic targets for lowering CVD. Furthermore, IL-6 inhibition may have a more favorable effect on pneumonia risk than IL-6R inhibition.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Medicine, General & Internal
Tycho R. Tromp, Merel L. Hartgers, G. Kees Hovingh, Antonio J. Vallejo-Vaz, Kausik K. Ray, Handrean Soran, Tomas Freiberger, Stefano Bertolini, Mariko Harada-Shiba, Dirk J. Blom, Frederick J. Raal, Marina Cuchel
Summary: Patients with homozygous familial hypercholesterolaemia (HoFH) globally face issues of late diagnosis, under-treatment, and high risk of premature ASCVD. The use of multiple lipid-lowering therapy regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival.
Article
Biochemistry & Molecular Biology
Julius L. Katzmann, Arjen J. Cupido, Ulrich Laufs
Summary: Recent developments in cardiovascular prevention research have shown successful treatments for LDL hypercholesterolemia, such as inhibiting the PCSK9 gene or using specific drugs. These methods have led to long-term reductions in LDL cholesterol levels and have the potential to fundamentally change our approach to cardiovascular prevention.
Letter
Cardiac & Cardiovascular Systems
Arjen J. Cupido, Jordan M. Kraaijenhof, Stephen Burgess, Folkert W. Asselbergs, G. Kees Hovingh, Dipender Gill
CIRCULATION-GENOMIC AND PRECISION MEDICINE
(2022)
Article
Cardiac & Cardiovascular Systems
Arjen J. Cupido, Folkert W. Asselbergs, A. Floriaan Schmidt, G. Kees Hovingh
Summary: This study found that genetically increased LDL-C has a sex-specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. The observations provide evidence that LDL-C might be a less important determinant of CVD in women compared with men.
JOURNAL OF THE AMERICAN HEART ASSOCIATION
(2022)
Review
Biochemistry & Molecular Biology
Arjen J. Cupido, Laurens F. Reeskamp, John J. P. Kastelein
CURRENT OPINION IN LIPIDOLOGY
(2017)
