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Molecular Genetics and Metabolism Sep 2018Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is an autosomal recessive disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase.... (Review)
Review
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is an autosomal recessive disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to the accumulation of specific glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS), which are mainly synthesized in the cartilage. Therefore, the substrates are stored primarily in the cartilage and its extracellular matrix (ECM), leading to a direct impact on bone development and successive systemic skeletal spondylepiphyseal dysplasia. The skeletal-related symptoms for MPS IVA include short stature with short neck and trunk, odontoid hypoplasia, spinal cord compression, tracheal obstruction, obstructive airway, pectus carinatum, restrictive lung, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. The degree of imbalance of growth in bone and other organs and tissues largely contributes to unique skeletal dysplasia and clinical severity. Diagnosis of MPS IVA needs clinical, radiographic, and laboratory testing to make a complete conclusion. To diagnose MPS IVA, total urinary GAG analysis which has been used is problematic since the values overlap with those in age-matched controls. Currently, urinary and blood KS and C6S, the enzyme activity of GALNS, and GALNS molecular analysis are used for diagnosis and prognosis of clinical phenotype in MPS IVA. MPS IVA can be diagnosed with unique characters although this disorder relates closely to other disorders in some characteristics. In this review article, we comprehensively describe clinical, radiographic, biochemical, and molecular diagnosis and clinical assessment tests for MPS IVA. We also compare MPS IVA to other closely related disorders to differentiate MPS IVA. Overall, imbalance of growth in MPS IVA patients underlies unique skeletal manifestations leading to a critical indicator for diagnosis.
Topics: Cartilage; Chondroitin Sulfates; Chondroitinsulfatases; Enzyme Replacement Therapy; Glycosaminoglycans; Humans; Keratan Sulfate; Mucopolysaccharidosis IV; Phenotype; Prognosis
PubMed: 29779902
DOI: 10.1016/j.ymgme.2018.05.004 -
Arteriosclerosis, Thrombosis, and... Dec 2023Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or... (Review)
Review
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent -acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
Topics: Humans; Acetylgalactosamine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Hypertension; Renin; Renin-Angiotensin System; RNA, Small Interfering
PubMed: 37855126
DOI: 10.1161/ATVBAHA.123.319897 -
Toxicologic Pathology Oct 2018Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine... (Review)
Review
Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine (GalNAc)-conjugated siRNAs (GalNAc-siRNAs), also referred to as RNA interference (RNAi) therapeutics, are currently in various stages of development, though none is yet approved. While the safety of ASOs has been the subject of extensive review, the nonclinical safety profiles of GalNAc-siRNAs have not been reported. With the exception of sequence differences that confer target RNA specificity, GalNAc-siRNAs are largely chemically uniform, containing limited number of phosphorothioate linkages, and 2'-O-methyl and 2'-deoxy-2'-fluoro ribose modifications. Here, we present the outcomes of short-term (3-5 week) rat and monkey weekly repeat-dose toxicology studies of six Enhanced Stabilization Chemistry GalNAc-siRNAs currently in clinical development. In nonclinical studies at supratherapeutic doses, these molecules share similar safety signals, with histologic findings in the organ of pharmacodynamic effect (liver), the organ of elimination (kidney), and the reticuloendothelial system (lymph nodes). The majority of these changes are nonadverse, partially to completely reversible, correlate well with pharmacokinetic parameters and tissue distribution, and often reflect drug accumulation. Furthermore, all GalNAc-siRNAs tested to date have been negative in genotoxicity and safety pharmacology studies.
Topics: Acetylgalactosamine; Animals; CHO Cells; Chromosome Aberrations; Cricetulus; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Liver; Lymphocytes; Macaca fascicularis; Mutagenicity Tests; RNA, Small Interfering; Rats, Sprague-Dawley; Species Specificity; Toxicity Tests, Subacute
PubMed: 30139307
DOI: 10.1177/0192623318792537 -
Expert Opinion on Biological Therapy Aug 2019The development of new biologic agents able to restore thrombin generation has become the focus of innovation in hemophilia management. There is growing interest in the... (Review)
Review
INTRODUCTION
The development of new biologic agents able to restore thrombin generation has become the focus of innovation in hemophilia management. There is growing interest in the proposal of novel, non-replacement therapy with alternative mechanisms of action and route of administration, hoping to solve still unmet needs in treatment of hemophilic patients with or without inhibitors.
AREAS COVERED
The review describes the new molecules, in particular the bi-specific antibody mimicking the coagulation function of FVIII and/or those which work by inhibiting the natural anticoagulants, their mechanism of action and the results of ongoing clinical trials.
EXPERT OPINION
Exciting results in enhancing the protection against bleeding and improving quality of life are emerging from clinical trials. However, these molecules with their mechanisms of action also open new problems. Treatment of bleeding and management of surgery in subjects with a rebalanced hemostasis may be difficult, especially for the lack of laboratory tests perfectly reflecting the coagulation status. A careful surveillance is required to evaluate the risk of thrombotic complication in patients with rebalanced hemostasis, in addition to understand whether these new products offer the same protection on joints as regular prophylaxis with the missing clotting factors.
Topics: Acetylgalactosamine; Animals; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Hemophilia A; Hemostasis; Humans; RNA, Small Interfering; Randomized Controlled Trials as Topic
PubMed: 31039049
DOI: 10.1080/14712598.2019.1614163 -
American Journal of Medical Genetics.... Nov 2022
Topics: Humans; Mucopolysaccharidoses; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase
PubMed: 35959767
DOI: 10.1002/ajmg.a.62934 -
Journal of Hepatology Aug 2019Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway... (Review)
Review
Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.
Topics: 5-Aminolevulinate Synthetase; Acetylgalactosamine; Bone Marrow Transplantation; Cholestyramine Resin; Genetic Therapy; Heme; Humans; Liver; Liver Transplantation; Porphyrias, Hepatic; Porphyrins; Pyrrolidines; Receptor, Melanocortin, Type 1; alpha-MSH
PubMed: 31102718
DOI: 10.1016/j.jhep.2019.05.003 -
Journal of Immunology Research 2015C-type lectin receptors (CLRs) on antigen-presenting cells (APCs) facilitate uptake of carbohydrate antigens for antigen presentation, modulating the immune response in... (Review)
Review
C-type lectin receptors (CLRs) on antigen-presenting cells (APCs) facilitate uptake of carbohydrate antigens for antigen presentation, modulating the immune response in infection, homeostasis, autoimmunity, allergy, and cancer. In this review, we focus on the role of the macrophage galactose type C-type lectin (MGL) in the immune response against self-antigens, pathogens, and tumor associated antigens (TAA). MGL is a CLR exclusively expressed by dendritic cells (DCs) and activated macrophages (MØs), able to recognize terminal GalNAc residues, including the sialylated and nonsialylated Tn antigens. We discuss the effects on DC function induced throughout the engagement of MGL, highlighting the importance of the antigen structure in the modulation of immune response. Indeed modifying Tn-density, the length, and steric structure of the Tn-antigens can result in generating immunogens that can efficiently bind to MGL, strongly activate DCs, mimic the effects of a danger signal, and achieve an efficient presentation in HLA classes I and II compartments.
Topics: Acetylgalactosamine; Antigen Presentation; Antigens, Bacterial; Antigens, Tumor-Associated, Carbohydrate; Antigens, Viral; Autoantigens; Dendritic Cells; Gene Expression; HLA Antigens; Humans; Immunologic Factors; Lectins, C-Type; Ligands; Macrophages; Neoplasms; Peptidomimetics; Signal Transduction
PubMed: 26839900
DOI: 10.1155/2015/450695 -
Journal of Inherited Metabolic Disease Jul 2021
Topics: Acetylgalactosamine; Homocysteine; Humans; Porphyria, Acute Intermittent; Pyrrolidines
PubMed: 34145602
DOI: 10.1002/jimd.12411 -
Methods in Molecular Biology (Clifton,... 2021Small interfering RNA (siRNA) is a clinically approved therapeutic modality, which has attracted widespread attention not only from basic research but also from...
Small interfering RNA (siRNA) is a clinically approved therapeutic modality, which has attracted widespread attention not only from basic research but also from pharmaceutical industry. As siRNA can theoretically modulate any disease-related gene's expression, plenty of siRNA therapeutic pipelines have been established by tens of biotechnology companies. The drug performance of siRNA heavily depends on the sequence, the chemical modification, and the delivery of siRNA. Here, we describe the rational design protocol of siRNA, and provide some modification patterns that can enhance siRNA's stability and reduce its off-target effect. Also, the delivery method based on N-acetylgalactosamine (GalNAc)-siRNA conjugate that is widely employed to develop therapeutic regimens for liver-related diseases is also recapitulated.
Topics: Acetylgalactosamine; Animals; Gene Transfer Techniques; HEK293 Cells; Hepatocytes; Humans; Liver; Liver Diseases; Mice, Inbred C57BL; Prealbumin; RNA Interference; RNA, Small Interfering; RNAi Therapeutics; Research Design; Toxicity Tests; Workflow; Mice
PubMed: 33928571
DOI: 10.1007/978-1-0716-1298-9_6 -
Pharmacological Research Nov 2021The growing use of short-interfering RNA (siRNA)-based therapeutics for viral diseases reflects the most recent innovations in anti-viral vaccines and drugs. These drugs... (Review)
Review
The growing use of short-interfering RNA (siRNA)-based therapeutics for viral diseases reflects the most recent innovations in anti-viral vaccines and drugs. These drugs play crucial roles in the fight against many hitherto incurable diseases, the causes, pathophysiologies, and molecular processes of which remain unknown. Targeted liver drug delivery systems are in clinical trials. The receptor-mediated endocytosis approach involving the abundant asialoglycoprotein receptors (ASGPRs) on the surfaces of liver cells show great promise. We here review N-acetylgalactosamine (GalNAc)-siRNA conjugates that treat viral diseases such as hepatitis B infection, but we also mention that novel, native conjugate-based, targeted siRNA anti-viral drugs may also cure several life-threatening diseases such as hemorrhagic cystitis, multifocal leukoencephalopathy, and severe acute respiratory syndrome caused by coronaviruses and human herpes virus.
Topics: Acetylgalactosamine; Animals; Humans; RNA Interference; RNA, Small Interfering; Virus Diseases; Viruses
PubMed: 34474100
DOI: 10.1016/j.phrs.2021.105864