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Drugs of Today (Barcelona, Spain : 1998) Jan 2021Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of...
Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of overproduction of heme precursors (hepatic or erythropoietic) or the main clinical manifestations (acute or cutaneous). The regulation of 5- (or δ)-aminolevulinic acid synthase 1 (ALAS1) plays a key role in the pathway of normal hepatic heme synthesis, providing insight into the pathophysiologic mechanisms and potential therapeutic targets for the treatment of the porphyrias. Givosiran (Givlaari; Alnylam Pharmaceuticals) is an ALAS1-directed small interfering RNA (siRNA) which has been developed for the treatment of acute hepatic porphyria (AHP). It was first approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with AHP, and it received also approval in the E.U. in 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.
Topics: Acetylgalactosamine; Adolescent; Adult; Child; Humans; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Pyrrolidines; United States
PubMed: 33594389
DOI: 10.1358/dot.2021.57.1.3230207 -
Advanced Drug Delivery Reviews May 2022The secreted mucus layer that lines and protects epithelial cells is conserved across diverse species. While the exact composition of this protective layer varies... (Review)
Review
The secreted mucus layer that lines and protects epithelial cells is conserved across diverse species. While the exact composition of this protective layer varies between organisms, certain elements are conserved, including proteins that are heavily decorated with N-acetylgalactosamine-based sugars linked to serines or threonines (O-linked glycosylation). These heavily O-glycosylated proteins, known as mucins, exist in many forms and are able to form hydrated gel-like structures that coat epithelial surfaces. In vivo studies in diverse organisms have highlighted the importance of both the mucin proteins as well as their constituent O-glycans in the protection and health of internal epithelia. Here, we summarize in vivo approaches that have shed light on the synthesis and function of these essential components of mucus.
Topics: Epithelial Cells; Glycosylation; Humans; Mucins; Mucus; Polysaccharides
PubMed: 35278522
DOI: 10.1016/j.addr.2022.114182 -
Expert Review of Clinical Pharmacology Apr 2022Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs,... (Review)
Review
INTRODUCTION
Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs, accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid and porphobilinogen, caused by enhanced activity of hepatic aminolevulinate synthase 1 (ALAS1), is associated with acute, potentially life-threatening neurovisceral attacks. Symptoms during and between attacks dramatically reduce patients' quality of life (QoL). Givosiran is the first mRNA-targeted treatment for AHPs, silencing ALAS1 expression.
AREAS COVERED
For givosiran, this review summarizes its chemistry, mechanism of action, pharmacokinetics, pharmacodynamics, safety, preclinical and clinical data in AHP, postmarketing surveillance, and regulatory status. A literature search of public and internal databases was performed, bibliographies of retrieved articles were manually searched to identify additional studies of relevance, and information was also provided by Alnylam Pharmaceuticals.
EXPERT OPINION
Givosiran is a small interfering RNA (siRNA) therapeutic that reduces hepatic activity of ALAS1 and decreases accumulation of neurotoxic porphyrin precursors in patients with AHPs, ultimately reducing the number of acute attacks and improving symptoms and QoL between attacks. As AHPs are lifelong diseases, long-term safety data are needed for givosiran as an siRNA-based therapy.
Topics: Acetylgalactosamine; Humans; Porphobilinogen Synthase; Porphyrias, Hepatic; Porphyrins; Pyrrolidines; Quality of Life; RNA, Small Interfering
PubMed: 35531651
DOI: 10.1080/17512433.2022.2075848 -
Expert Opinion on Drug Delivery Apr 2022miRNA-derivative clinical nucleotide drugs (mdCNDs) effectively treat several diseases, with numerous undergoing clinical trials. In early-stage trials in disease... (Review)
Review
INTRODUCTION
miRNA-derivative clinical nucleotide drugs (mdCNDs) effectively treat several diseases, with numerous undergoing clinical trials. In early-stage trials in disease therapeutics, such as malignant pleural mesothelioma and hepatic virus C infection, mdCND's therapeutic potency is undeniably good for effectiveness and safety.
AREAS COVERED
Fifteen mdCNDs undergoing clinical trials are introduced in this review. MiRNA modifications methods have been summarized, including phosphorothioate, cholesterol, locked nucleic acid, 2'-O-methyl, N,N-diethyl-4-(4-nitronaphthalen1-ylazo)-phenylamine modifications, and many more. Moreover, delivery systems, including self-assembled, inorganic ions nanoparticles, exosomes, and lipid-based nanosystems for mdCNDs targeted delivery, are presented. Among that, EnGeneIC, N-Acetylgalactosamine, liposomal nanoparticles, and cholesterol-conjugated for mdCNDs delivery are currently undergoing clinical trials. The pH, light, temperature, redox-responsive, enzyme, and specific-substance modes to trigger the release of miRNAs to target sites on-demand and the prospects of mdCNDs are discussed in this review.
EXPERT OPINION
mdNCDs are one type of promising clinical drugs, however, it is still in the infancy. During the development process, it is imperative to advance in modifying miRNAs, especially at the 5'-end, to enhance targetability and stability against nucleases, develop a stimuli-responsive mode to control the release of mdCNDs to tissue cell-type-specific sites.
Topics: Drug Carriers; Drug Delivery Systems; MicroRNAs; Nanoparticles; Nucleotides
PubMed: 35387533
DOI: 10.1080/17425247.2022.2063835 -
The FEBS Journal Aug 2019Chondroitin sulfate E (CS-E) is a glycosaminoglycan containing type-E disaccharide units (sulfated at C-4 and C-6 of N-acetylgalactosamine). CS-E is covalently linked to... (Review)
Review
Chondroitin sulfate E (CS-E) is a glycosaminoglycan containing type-E disaccharide units (sulfated at C-4 and C-6 of N-acetylgalactosamine). CS-E is covalently linked to a core protein to form chondroitin sulfate proteoglycans (PGs) that are secreted or associated with the plasma membrane of several types of cells. CS-E-containing PGs selectively interact with growth factors and chemokines and control various cellular and/or tissue processes. Angiogenesis is a process that is highly regulated in physiological conditions but deregulated in pathologies, leading to excess or deficient blood vessel formation. Angiogenesis regulation is orchestrated by numerous growth factors, such as vascular endothelial growth factor A, fibroblast growth factors and pleiotrophin, whose functions can be affected by CS-containing PGs. In the present review, we focus on the emerging area of CS-mediated angiogenesis and particularly on the critical assessment of data related to a potential role of CS-E in controlling endothelial cell functions, focusing on angiogenesis regulation and vascular homeostasis in health and disease.
Topics: Animals; Blood Vessels; Chemokines; Chondroitin Sulfates; Humans; Intercellular Signaling Peptides and Proteins; Neovascularization, Physiologic
PubMed: 30932321
DOI: 10.1111/febs.14830 -
International Journal of Biological... 2022O-glycosylation is a widespread post-translational modification of proteins. Aberrant O-glycosylation is a hallmark of cancer. Here, we show that the polypeptide...
O-glycosylation is a widespread post-translational modification of proteins. Aberrant O-glycosylation is a hallmark of cancer. Here, we show that the polypeptide N-acetylgalactosamine-transferase 1 () is frequently upregulated in gastric cancer and is correlated with poor survival. Overexpression of promoted, whereas knockdown suppressed proliferation, migration, and invasion of gastric cancer cells and . Mechanistically, enhances aberrant initiation of O-glycosylation and results in CD44 glycoproteins modified with abundant Tn antigens, thereby activating the Wnt/β-catenin signaling pathway. Collectively, this study demonstrates that overexpression in gastric cancer promotes the Wnt/β-catenin signaling pathway via abnormal O-glycosylation of CD44 to enhance malignancy, providing a novel strategy for the development of therapeutic reagents against gastric cancer.
Topics: Humans; Wnt Signaling Pathway; Stomach Neoplasms; Glycosylation; Phenotype; Hyaluronan Receptors
PubMed: 36439876
DOI: 10.7150/ijbs.73431 -
Cell Surface (Amsterdam, Netherlands) Dec 2023Half a century after their discovery, polymers of -acetylgalactosamine produced by the Aspergilli have garnered new interest as mediators of fungal virulence. Recent... (Review)
Review
Half a century after their discovery, polymers of -acetylgalactosamine produced by the Aspergilli have garnered new interest as mediators of fungal virulence. Recent work has focused on the secreted and cell wall-associated heteropolymer, galactosaminogalactan (GAG). This polymer, composed of galactose (Gal) and partially deacetylated -acetylgalactosamine (GalNAc), plays a role in a variety of pathogenic processes including biofilm formation, immune modulation and evasion, and resistance to antifungals. Given its many potential contributions to fungal pathogenesis, GAG is a promising therapeutic target for novel antifungal strategies. As such, several studies have sought to elucidate the biosynthetic pathways required for GAG production and secretion. Herein we review the progress made in the understanding of the molecular mechanisms underlying GAG synthesis and identify several gaps in our understanding of this process.
PubMed: 36691652
DOI: 10.1016/j.tcsw.2023.100095 -
Methods in Molecular Biology (Clifton,... 2020Tachylectin-2, a 27-kDa protein consisting of a five-bladed β-propeller structure, is purified by three steps of chromatography, including dextran sulfate-Sepharose...
Tachylectin-2, a 27-kDa protein consisting of a five-bladed β-propeller structure, is purified by three steps of chromatography, including dextran sulfate-Sepharose CL-6B, CM-Sepharose CL-6B, and Mono S. Three isolectins of tachylectin-2 including tachylectin-2a, -2b, and -2c are purified. These isolectins exhibit hemagglutinating activity against human A-type erythrocytes in a Ca-independent manner with tachylectin-2b showing the highest activity. Tachylectin-2b specifically agglutinates Staphylococcus saprophyticus KD. The tachylectin-2b-mediated hemagglutination is inhibited in the presence of GlcNAc and GalNAc. The association constants for GlcNAc and GalNAc are K = 1.95 × 10 M and K = 1.11 × 10 M, respectively. Ultracentrifugation analysis shows that tachylectin-2b is present in monomer form in solution.
Topics: Acetylgalactosamine; Acetylglucosamine; Agglutination Tests; Animals; Calcium; Chromatography; Erythrocytes; Hemagglutination; Horseshoe Crabs; Humans; Lectins; Protein Isoforms; Protein Multimerization; Staphylococcus saprophyticus
PubMed: 32306338
DOI: 10.1007/978-1-0716-0430-4_30 -
Expert Opinion on Drug Metabolism &... Dec 2021Inclisiran is a small interfering RNA that inhibits hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9) which results in reduction of circulating... (Review)
Review
INTRODUCTION
Inclisiran is a small interfering RNA that inhibits hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9) which results in reduction of circulating low-density lipoprotein cholesterol (LDL-C). It can be used alone or in combination with statins or other lipid-lowering therapy.
AREAS COVERED
In this article, we review the pharmacokinetics, pharmacodynamics and clinical efficacy of inclisiran based on the published literature.
EXPERT OPINION
Inclisiran is a chemically stabilized duplex RNA conjugated with triantennary N-acetylgalactosamine which facilitates rapid and selective liver uptake and the drug is almost entirely removed from the circulation within 24 hours after subcutaneous injection. The duration of action is impressively prolonged and after doses of 300 mg on days one and 90, the dose can be repeated every six months to maintain a durable reduction of LDL-C by about 50%. The efficacy and safety are similar to the monoclonal antibodies targeting PCSK9, evolocumab and alirocumab, and injection site reactions are infrequent and generally mild. The cardiovascular outcome study with inclisiran is ongoing and other long term safety data are keenly awaited. The infrequent dosing regimen offers a major advantage to improve long term compliance and inclisiran may be extensively adopted depending on the cost.
Topics: Anticholesteremic Agents; Cardiovascular Diseases; Humans; Proprotein Convertase 9; RNA, Small Interfering
PubMed: 35025707
DOI: 10.1080/17425255.2021.2029402 -
Arteriosclerosis, Thrombosis, and... Dec 2021While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their... (Review)
Review
While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their unfavorable pharmacokinetics and intrinsic capacity to mobilize innate immune responses, were limiting widespread clinical use. However, these major setbacks have been tackled by breakthroughs in chemistry, stability and delivery. When aiming an intervention hepatic targets, such as lipid and sugar metabolism, coagulation, not to mention cancer and virus infection, introduction of N-acetylgalactosamine aided targeting technology has advanced the field profoundly and by now a dozen of N-acetylgalactosamine therapeutics for these indications have been approved for clinical use or have progressed to clinical trial stage 2 to 3 testing. This technology, in combination with major advances in oligonucleotide stability allows safe and durable intervention in targets that were previously deemed undruggable, such as Lp(a) and PCSK9 (proprotein convertase subtilisin/kexin type 9), at high efficacy and specificity, often with as little as 2 doses per year. Their successful use even the most visionary would not have predicted 2 decades ago. Here, we will review the evolution of N-acetylgalactosamine technology. We shall outline their fundamental design principles and merits, and their application for the delivery of oligonucleotide therapeutics to the liver. Finally, we will discuss the perspectives of N-acetylgalactosamine technology and propose directions for future research in receptor targeted delivery of these gene medicines.
Topics: Acetylgalactosamine; Cardiovascular Diseases; Drug Delivery Systems; Genetic Therapy; Hepatocytes; Humans; Liver; Oligonucleotides; RNAi Therapeutics
PubMed: 34645280
DOI: 10.1161/ATVBAHA.121.316290