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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 -
Journal of Separation Science Jan 2018O-Glycosylation, which refers to the glycosylation of the hydroxyl group of side chains of Serine/Threonine/Tyrosine residues, is one of the most common... (Review)
Review
O-Glycosylation, which refers to the glycosylation of the hydroxyl group of side chains of Serine/Threonine/Tyrosine residues, is one of the most common post-translational modifications. Compared with N-linked glycosylation, O-glycosylation is less explored because of its complex structure and relatively low abundance. Recently, O-glycosylation has drawn more and more attention for its various functions in many sophisticated biological processes. To obtain a deep understanding of O-glycosylation, many efforts have been devoted to develop effective strategies to analyze the two most abundant types of O-glycosylation, i.e. O-N-acetylgalactosamine and O-N-acetylglucosamine glycosylation. In this review, we summarize the proteomics workflows to analyze these two types of O-glycosylation. For the large-scale analysis of mucin-type glycosylation, the glycan simplification strategies including the ''SimpleCell'' technology were introduced. A variety of enrichment methods including lectin affinity chromatography, hydrophilic interaction chromatography, hydrazide chemistry, and chemoenzymatic method were introduced for the proteomics analysis of O-N-acetylgalactosamine and O-N-acetylglucosamine glycosylation.
Topics: Animals; CHO Cells; Cattle; Cell Line; Chromatography, Affinity; Cricetinae; Cricetulus; Drosophila; Glycosylation; HEK293 Cells; HeLa Cells; Humans; Hydrazines; Jurkat Cells; Lectins; MCF-7 Cells; Mice; Phosphorylation; Polysaccharides; Protein Processing, Post-Translational; Proteins; Proteomics; Serine; Tyrosine
PubMed: 28988430
DOI: 10.1002/jssc.201700834 -
Nucleic Acids Research May 2024RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in...
RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in many tissues. The route of administration and chemical architecture are the primary drivers of oligonucleotide tissue distribution, including siRNAs. Independently of the nature and type, oligonucleotides are eliminated from the body through clearance tissues, where their unintended accumulation may result in undesired gene modulation. Divalent siRNAs (di-siRNAs) administered into the CSF induce robust gene silencing throughout the central nervous system (CNS). Upon clearance from the CSF, they are mainly filtered by the kidneys and liver, with the most functionally significant accumulation occurring in the liver. siRNA- and miRNA-induced silencing can be blocked through substrate inhibition using single-stranded, stabilized oligonucleotides called antagomirs or anti-siRNAs. Using APOE as a model target, we show that undesired di-siRNA-induced silencing in the liver can be mitigated through administration of liver targeting GalNAc-conjugated anti-siRNAs, without impacting CNS activity. Blocking unwanted hepatic APOE silencing achieves fully CNS-selective silencing, essential for potential clinical translation. While we focus on CNS/liver selectivity, coadministration of differentially targeting siRNA and anti-siRNAs can be adapted as a strategy to achieve tissue selectivity in different organ combinations.
Topics: Animals; Humans; Male; Mice; Acetylgalactosamine; Antagomirs; Apolipoproteins E; Central Nervous System; Gene Silencing; Liver; Mice, Inbred C57BL; MicroRNAs; RNA Interference; RNA, Small Interfering
PubMed: 38348876
DOI: 10.1093/nar/gkae100 -
Expert Opinion on Drug Metabolism &... Jun 2019: Triantennary N-acetyl galactosamine (GalNAc) - conjugated antisense oligonucleotides (ASOs) have demonstrated improved hepatocyte uptake and pharmacologic activity... (Review)
Review
: Triantennary N-acetyl galactosamine (GalNAc) - conjugated antisense oligonucleotides (ASOs) have demonstrated improved hepatocyte uptake and pharmacologic activity over their parent unconjugated ASOs in animals and . : In this review, the ADME (absorption, distribution, metabolism, and excretion) characteristics of GalNAc-conjugated ASOs in animals and in are summarized, and their clinical relevance is evaluated from the clinical pharmacology perspectives. : ASOs distribute to tissues via receptor-mediated processes, and conjugation to a ligand specific to certain cell types can improve target tissue delivery. GalNAc-conjugation represents a good example on this regard and has demonstrated ideal characteristics of a prodrug to target delivery of ASOs to hepatocytes via the asialoglycoprotein receptor (ASGPR). The improved potency and safety margin permit more flexible dosing (e.g. monthly or less frequently if needed) taking full advantage of the long half-life of the parent ASO in . However, while still speculative, it should be noted that ASGPR-mediated uptake could become nonlinear with dose and factors that impact ASGPR expression or compete with ASGPR-mediated uptake could potentially affect the uptake of GalNAc-conjugated ASOs, further studies are warranted.
Topics: Acetylgalactosamine; Animals; Asialoglycoprotein Receptor; Drug Delivery Systems; Half-Life; Hepatocytes; Humans; Oligonucleotides, Antisense; Prodrugs
PubMed: 31144994
DOI: 10.1080/17425255.2019.1621838 -
Pathology, Research and Practice Sep 2019Arylsulfatases are lysosomal enzymes with important roles in the cell metabolism. Several subtypes of arylsulfatase are known, from A to K. Congenital deficiencies of... (Review)
Review
Arylsulfatases are lysosomal enzymes with important roles in the cell metabolism. Several subtypes of arylsulfatase are known, from A to K. Congenital deficiencies of arylsulfatases, especially A (ARSA) and B (ARSB), can induce metabolic disorders such as metachromatic leucodystrophy (ARSA deficiency) and Maroteaux-Lamy syndrome (ARSB deficiency). ARSA and ARSB pseudodeficiencies were recently described but their exact roles are far to be known. The aim of this review was to synthesize the literature data, combined with personal results, regarding the roles of ARSA and ARSB in non-tumor disorders but also carcinogenesis. Few than 50 published papers regard ARSA and ARSB expression in cancer. They suggest decreased activity of these arylsulfatases in most of carcinomas, compared with normal tissues. However, the clinical impact is still unknown. Further complex studies are necessary to be done, to understand the role of ARSA and ARSB expression in cancer.
Topics: Animals; Cerebroside-Sulfatase; Humans; Lysosomal Storage Diseases; N-Acetylgalactosamine-4-Sulfatase; Neoplasms
PubMed: 31262576
DOI: 10.1016/j.prp.2019.152516 -
The Journal of Biological Chemistry Jul 2023A primary pathology of Alzheimer's disease (AD) is amyloid β (Aβ) deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy...
A primary pathology of Alzheimer's disease (AD) is amyloid β (Aβ) deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal Aβ precursor protein (APP). Although vascular amyloid deposits' origins remain unclear, endothelial APP expression in APP knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APP's importance. Furthermore, two types of endothelial APP-highly O-glycosylated APP and hypo-O-glycosylated APP-have been biochemically identified, but only the former is cleaved for Aβ production, indicating the critical relationship between APP O-glycosylation and processing. Here, we analyzed APP glycosylation and its intracellular trafficking in neurons and endothelial cells. Although protein glycosylation is generally believed to precede cell surface trafficking, which was true for neuronal APP, we unexpectedly observed that hypo-O-glycosylated APP is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires additional O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced Aβ production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Cerebral Amyloid Angiopathy; Endothelial Cells; Glycosylation; Protein Transport; Neurons; Golgi Apparatus; Acetylgalactosamine
PubMed: 37302553
DOI: 10.1016/j.jbc.2023.104905 -
Biochemical Society Transactions Feb 2016Protein O-GalNAcylation is an abundant post-translational modification and predicted to occur in over 80% of the proteins passing through the Golgi apparatus. This... (Review)
Review
Protein O-GalNAcylation is an abundant post-translational modification and predicted to occur in over 80% of the proteins passing through the Golgi apparatus. This modification is driven by 20 polypeptide GaINAc (N-acetylgalactosamine)-transferases (GalNAc-Ts), which are unique in that they possess both catalytic and lectin domains. The peptide substrate specificities of GalNAc-Ts are still poorly defined and our understanding of the sequence and structural features that direct O-glycosylation of proteins is limited. Part of this may be attributed to the complex regulation by coordinated action of multiple GalNAc-T isoforms, and part of this may also be attributed to the two functional domains of GalNAc-Ts that both seems to be involved in directing the substrate specificities. Recent studies have resulted in 3D structures of GalNAc-Ts and determination of the reaction mechanism of this family of enzymes. Key advances include the trapping of binary/ternary complexes in combination with computational simulations and AFM/small-SAXS experiments, which have allowed for the dissection of the reaction coordinates and the mechanism by which the lectin domains modulate the glycosylation. These studies not only broaden our knowledge of the modes-of-action of this family of enzymes but also open up potential avenues for the rational design of effective and selective inhibitors of O-glycosylation.
Topics: Acetylgalactosamine; Animals; Biocatalysis; Glycosylation; Humans; Models, Molecular; N-Acetylgalactosaminyltransferases; Protein Structure, Tertiary
PubMed: 26862189
DOI: 10.1042/BST20150178 -
Drugs May 2021Givosiran (Givlaari) is an δ-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) approved for the treatment of acute hepatic porphyria (AHP).... (Review)
Review
Givosiran (Givlaari) is an δ-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) approved for the treatment of acute hepatic porphyria (AHP). In the phase 3 ENVISION trial, givosiran significantly reduced the annualized rate of composite porphyria attacks (i.e. attacks requiring hospitalization, urgent healthcare visit or intravenous hemin administration at home) compared with placebo in patients with recurrent acute intermittent porphyria (the most common type of AHP) attacks. Givosiran also improved several other outcomes, including hemin use and pain (the cardinal symptom of AHP). While generally well tolerated with an acceptable safety profile, the drug may increase the risk of hepatic and kidney adverse events. Givosiran offers the convenience of once-monthly subcutaneous administration. Available evidence indicates that givosiran is an important newer therapeutic option for patients with AHP and severe recurrent attacks.
Topics: 5-Aminolevulinate Synthetase; Acetylgalactosamine; Acute Kidney Injury; Chemical and Drug Induced Liver Injury; Drug Interactions; Hemin; Hospitalization; Humans; Pain; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Pyrrolidines; RNA, Small Interfering; Randomized Controlled Trials as Topic; Severity of Illness Index
PubMed: 33871817
DOI: 10.1007/s40265-021-01511-3 -
International Journal of Molecular... Dec 2021Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due... (Review)
Review
Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10-15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.
Topics: Chondroitin Sulfates; Enzyme Replacement Therapy; Glycosaminoglycans; Humans; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase
PubMed: 34948256
DOI: 10.3390/ijms222413456