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Clinical pharmacology of siRNA therapeutics: current status and future prospects
Expert Rev Clin Pharmacol. 2022 Oct 17. doi: 10.1080/17512433.2022.2136166. Online ahead of print.ABSTRACTINTRODUCTION: Small interfering RNA (siRNA) has emerged as a powerful tool for post-transcriptional downregulation of multiple genes for various therapies. Naked siRNA molecules are surrounded by several barriers that tackle their optimum delivery to target tissues such as limited cellular uptake, short circulation time, degradation by endonucleases, glomerular filtration, and capturing by the reticuloendothelial system (RES).AREAS COVERED: This review provides insights into studies that investigate various siRNA-based...
Source: Expert Review of Clinical Pharmacology - October 17, 2022 Category: Drugs & Pharmacology Authors: Ahmed Khaled Abosalha Jacqueline Boyajian Waqar Ahmad Paromita Islam Merry Ghebretatios Sabrina Schaly Rahul Thareja Karan Arora Satya Prakash Source Type: research

Therapeutic siRNA: State-of-the-Art and Future Perspectives
This article reviews the knowledge on siRNA design and chemical modification, as well as issues related to siRNA delivery that may be addressed using different delivery systems. Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy. Notably, this may also cover otherwise un-druggable diseases, the definition of non-coding RNAs as targets, and novel concepts of personalized and combination treatment regimens.
Source: BioDrugs - August 23, 2022 Category: Drugs & Pharmacology Source Type: research

Cancers, Vol. 14, Pages 3162: Knockdown of 15-bp Deletion-Type v-raf Murine Sarcoma Viral Oncogene Homolog B1 mRNA in Pancreatic Ductal Adenocarcinoma Cells Repressed Cell Growth In Vitro and Tumor Volume In Vivo
In this study, siRNA was designed for the targeted knockdown of 15-bp deletion-type BRAF mRNA. This siRNA repressed the phosphorylation of extracellular-signal-regulated kinase proteins downstream of BRAF and suppressed cell growth in vitro and in vivo. Furthermore, siRNAs with 2′-O-methyl modifications at positions 2–5 reduce the seed-dependent off-target effects, as confirmed by reporter and microarray analyses. Thus, such siRNA is a promising candidate therapy for 15-bp deletion-type BRAF-induced tumorigenesis.
Source: Cancers - June 28, 2022 Category: Cancer & Oncology Authors: Jiaxuan Song Yoshiaki Kobayashi Yoshimasa Asano Atsushi Sato Hiroaki Taniguchi Kumiko Ui-Tei Tags: Article Source Type: research

Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran
AbstractIn November 2019 givosiran became the second small interfering RNA (siRNA)-based drug to receive US Food and Drug Administration (FDA) approval, it has been developed for the treatment of acute intermittent porphyria (AIP), a disorder characterized by life-threatening acute neurovisceral attacks. The  porphyrias are a group of disorders in which enzymatic deficiencies in heme production lead to toxic accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are involved in the neurovisceral attacks. Givosiran acts as a conventional siRNA to trigger RNA interference (RNAi) -mediated gene sile...
Source: Molecular Diagnosis and Therapy - December 1, 2019 Category: Molecular Biology Source Type: research

Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran
AbstractIn 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class that  results in the effect first described by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present with mutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulatio...
Source: Molecular Diagnosis and Therapy - November 6, 2019 Category: Molecular Biology Source Type: research

Patisiran for the treatment of patients with familial amyloid polyneuropathy.
Authors: Rizk M, Tüzmen S Abstract Onpattro, also commonly known as patisiran, is a small interfering RNA (siRNA) molecule packaged within a lipid nanoparticle and is transported into the cell to target transthyretin gene (TTR) messenger mRNA (mRNA) by attaching to its complementary sequence. The target mRNA is degraded and both mutant and wild-type amyloid transthyretin (ATTR) protein production becomes suppressed. This drug was developed by Alnylam Pharmaceuticals to treat a rare disease called hereditary ATTR (hATTR) amyloidosis. This disease develops as a result of the deposition of toxic aggregates of misfold...
Source: Drugs of Today - May 28, 2019 Category: Drugs & Pharmacology Tags: Drugs Today (Barc) Source Type: research

Gene Therapy Leaves a Vicious Cycle
Reena Goswami1, Gayatri Subramanian2, Liliya Silayeva1, Isabelle Newkirk1, Deborah Doctor1, Karan Chawla2, Saurabh Chattopadhyay2, Dhyan Chandra3, Nageswararao Chilukuri1 and Venkaiah Betapudi1,4* 1Neuroscience Branch, Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen, MD, United States 2Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States 3Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States 4Department of Physiology and Biophysics, Case Western Reserve University, Clev...
Source: Frontiers in Oncology - April 23, 2019 Category: Cancer & Oncology Source Type: research

Identification of KX2-391 as an inhibitor of HBV transcription by a recombinant HBV-based screening assay
This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection. Among them, KX2-391, a non-ATP-competitive inhibitor of SRC kinase and tubulin polymerization, was identified as a lead candidate for an anti-HBV drug. Treatment of sodium taurocholate cotransporting polypeptide (NTCP) transduced-HepG2 (HepG2-NTCP) or primary human hepatocytes with KX2-391 suppressed HBV replication in a dose-dependent manner. The anti-HBV activity of KX2-391 appeared not to depend on SRC kinase activity be...
Source: Antiviral Therapy - June 16, 2017 Category: Virology Source Type: research

Identification of KX2-391 as an inhibitor of HBV transcription by a recombinant HBV-based screening assay.
This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection. Among them, KX2-391, a non-ATP-competitive inhibitor of SRC kinase and tubulin polymerization, was identified as a lead candidate for an anti-HBV drug. Treatment of sodium taurocholate cotransporting polypeptide (NTCP) transduced-HepG2 (HepG2-NTCP) or primary human hepatocytes with KX2-391 suppressed HBV replication in a dose-dependent manner. The anti-HBV activity of KX2-391 appeared not to depend on SRC kinase activity be...
Source: Antiviral Research - June 14, 2017 Category: Virology Authors: Harada K, Nishitsuji H, Ujino S, Shimotohno K Tags: Antiviral Res Source Type: research

Synergistic anti‐myeloma activity of the proteasome inhibitor marizomib and the IMiD® immunomodulatory drug pomalidomide
Abstract The proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment o...
Source: British Journal of Haematology - October 12, 2015 Category: Hematology Authors: Deepika S. Das, Arghya Ray, Yan Song, Paul Richardson, Mohit Trikha, Dharminder Chauhan, Kenneth C. Anderson Tags: Research Paper Source Type: research

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