A biological guide to glycosaminoglycans: current perspectives and pending questions

FEBS Journal, Journal Year: 2024, Volume and Issue: 291(15), P. 3331 - 3366

Published: March 18, 2024

Mammalian glycosaminoglycans (GAGs), except hyaluronan (HA), are sulfated polysaccharides that covalently attached to core proteins form proteoglycans (PGs). This article summarizes key biological findings for the most widespread GAGs, namely HA, chondroitin sulfate/dermatan sulfate (CS/DS), keratan (KS), and heparan (HS). It focuses on major processes remain be deciphered get a comprehensive view of mechanisms mediating GAG functions. They include regulation biosynthesis postsynthetic modifications in heparin (HP) HS, composition, heterogeneity, function tetrasaccharide linkage region its role disease, functional characterization new PGs recently identified by glycoproteomics, selectivity interactions mediated chains, display chains at cell surface their impact availability activity soluble ligands, move through glycocalyx layer reach receptors, human profile health roles GAGs particular (syndecans, decorin, biglycan) involved cancer, inflammation, fibrosis, possible use as disease biomarkers, design inhibitors targeting biosynthetic enzymes GAG-protein develop novel therapeutic approaches.

Language: Английский

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Roles of the Oxytocin Receptor (OXTR) in Human Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3887 - 3887

Published: Feb. 15, 2023

The oxytocin receptor (OXTR), encoded by the OXTR gene, is responsible for signal transduction after binding its ligand, oxytocin. Although this signaling primarily involved in controlling maternal behavior, it was demonstrated that also plays a role development of nervous system. Therefore, not surprise both ligand and are modulation behaviors, especially those related to sexual, social, stress-induced activities. As case every regulatory system, any disturbances structures or functions may lead various diseases regulated functions, which include either mental problems (autism, depression, schizophrenia, obsessive-compulsive disorders) functioning reproductive organs (endometriosis, uterine adenomyosis, premature birth). Nevertheless, abnormalities connected other diseases, including cancer, cardiac disorders, osteoporosis, obesity. Recent reports indicated changes levels formation aggregates influence course some inherited metabolic such as mucopolysaccharidoses. In review, involvement dysfunctions polymorphisms different summarized discussed. analysis published results led us suggest expression abundance activity specific individual but rather they processes (mostly behavioral changes) might modulate disorders. Moreover, possible explanation discrepancies effects gene methylation on proposed.

Language: Английский

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Current and Emerging Therapies for Lysosomal Storage Disorders

Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Language: Английский

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Allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis patients: a single-center experience and assessment of quality of life

˜The œItalian Journal of Pediatrics/Italian journal of pediatrics, Journal Year: 2025, Volume and Issue: 51(1)

Published: March 18, 2025

Allogeneic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for patients with mucopolysaccharidoses (MPS). We investigate the efficacy and improvements in quality of life HSCT pediatric MPS. A retrospective analysis data from 46 cases MPS single institution China was conducted. The cohort included 9 I, 16 II, 15 IVA 6 VI. median age at diagnosis 2.59 years. 3.80 follow-up time 3.1 years (range, 0.8-8.1 years) 43 were alive. incidence grades II IV aGVHD 17.4%, wherein III 4.3%. moderate-to-severe cGVHD 6.5%. GAGs urinary excretion decreased enzyme activity levels reached normal. After HSCT, multiple bone dysplasia, upper-airway obstruction recurrent otitis media significantly improved; vision, corneal clouding, cardiovascular disease, hepatosplenomegaly hydrocephalus improved or remained stable; neurological symptoms stable most but progressed others; IH/S nearly normal growth rate height weight. Meanwhile, IH, VI poor after HSCT. Activities Daily Living (ADL) scores ADL severe phenotypes lower than health control subjects attenuated phenotypes. is good therapeutic improves patients. provide better outcome

Language: Английский

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Functional Analysis of Complex Structural and Splice‐Altering Variants in the ARSB Gene Towards the Personalized Antisense‐Based Therapy for Mucopolysaccharidosis Type VI Patients

Human Mutation, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Mucopolysaccharidosis Type VI (MPS VI) is a lysosomal storage disorder associated with biallelic pathogenic variants in the ARSB gene. Herein, we present three patients biochemical and clinical pictures of MPS VI, for whom routine molecular genetic analysis using Sanger sequencing failed to identify one or both causative variants. RNA patients’ samples revealed alterations wild‐type mRNA isoform all cases, case required further whole genome sequencing. As result, identified complex structural variant, which 52‐kb insertion LHFPL2 gene fragment Intron 4, derived from nonallelic homologous recombination leading premature transcription termination, recurrent deep intronic variant pseudoexon activation an intragenic deletion altering integrity splicing Exon 2. Using minigene‐based cellular model, demonstrated that can be efficiently blocked by antisense molecules incorporated into modified U7 small nuclear RNAs circular RNAs. The same approach was used block overlapping polymorphic increase amount approximately twofold.

Language: Английский

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mRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate Synthesis

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1273 - 1273

Published: Feb. 1, 2025

Mucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to lack an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt new approach in genetic medicine, substrate reduction therapy (gSRT), counteract this neurological disorder. Briefly, used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), target synthesis accumulated compounds at molecular level, downregulating specific gene involved first step HS biosynthesis, XYLT1. Our goal was reduce production and, consequently, accumulation. Initially, five ASOs were designed and their potential decrease XYLT1 mRNA levels tested patient-derived fibroblasts. Subsequent analyses focused on two best performing molecules alone. The results showed high inhibition (around 90%), xylosyltransferase I (XT-I) protein 6 10 days after transfection (up 21% 32%, respectively). Overall, our highly promising may represent initial towards development therapeutic option not only MPS IIIC, but virtually every other III form. Ultimately, same principle also apply neuropathic MPS.

Language: Английский

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Advancing CNS Therapeutics: Enhancing Neurological Disorders with Nanoparticle-Based Gene and Enzyme Replacement Therapies

International Journal of Nanomedicine, Journal Year: 2025, Volume and Issue: Volume 20, P. 1443 - 1490

Published: Feb. 1, 2025

Abstract: Given the complexity of central nervous system (CNS) and diversity neurological conditions, increasing prevalence disorders poses a significant challenge to modern medicine. These disorders, ranging from neurodegenerative diseases psychiatric not only impact individuals but also place substantial burden on healthcare systems society. A major obstacle in treating these conditions is blood-brain barrier (BBB), which restricts passage therapeutic agents brain. Nanotechnology, particularly use nanoparticles (NPs), offers promising solution this challenge. NPs possess unique properties such as small size, large surface area, modifiable characteristics, enabling them cross BBB deliver drugs directly affected brain regions. This review focuses application gene therapy enzyme replacement (ERT) for disorders. Gene involves altering or manipulating expression can be enhanced by designed carry various genetic materials. Similarly, improve efficacy ERT lysosomal storage (LSDs) facilitating delivery brain, overcoming issues like immunogenicity instability. Taken together, explores potential revolutionizing treatment options highlighting their advantages future directions rapidly evolving field. Keywords: system, nanoparticle, therapy,

Language: Английский

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Oral trehalose improves histological and behavior symptoms of mucopolysaccharidosis type II in iduronate 2-sulfatase deficient mice

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 10, 2025

Mucopolysaccharidosis type II (MPS II) is caused by a deficiency in iduronate-2-sulfatase (Ids), an enzyme that catabolizes glycosaminoglycan (GAG). Ids insufficiency results the accumulation of GAG various organs, ultimately resulting multisystemic disease. Trehalose, non-reducing disaccharide, has shown protective effects against diseases. However, its potential utility through oral administration MPS not yet been explored. In present study, to investigate efficacy trehalose Ids-knock-out (KO) mice, Ids-KO and wild (WT) mice were treated with 2% dissolved distilled water ad libitum for 24 weeks. Histological analysis revealed almost all tissues from exhibited abnormal changes, including large vacuolization, inflammatory cell infiltration, deposition. significantly suppressed levels, inflammation apoptosis spleen brain. Additionally, considerably improved cognitive functions, such as short-term spatial learning working memory, alongside limited improvements walking capacity mice. These suggest can reduce accumulation, vacuolization number apoptotic cells pathological brain, improving spontaneous alteration behavior could be promising treatment option II.

Language: Английский

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Efficacy of different treatment strategies in patients with mucopolysaccharidosis: a systematic review and network meta-analysis of randomized controlled trials

Orphanet Journal of Rare Diseases, Journal Year: 2025, Volume and Issue: 20(1)

Published: May 2, 2025

Abstract This systematic review of randomized controlled trials (RCT) was conducted to evaluate the efficacy enzyme replacement therapy (ERT) for patients with mucopolysaccharidosis (MPS). We systematically searched PubMed, Embase, Web Science, and Cochrane databases up August 22, 2023. Study design, interventions, outcome data were extracted. Continuous variable random-effects network meta-analysis performed. The included 23 studies involving 1,047 people MPS I–VI. In I, urinary glycosaminoglycan (uGAG) level significantly reduced in who took 2 mg/kg/week pentosan polysulfate (-2.66, 95% confidence interval (CI)[-3.86, -1.46]) compared those 1 mg/kg/week. II, placebo group, significant reduction observed uGAG (-270.77, CI[-406.57, -139.71]) cerebrospinal fluid (CSF) GAG (-1,385.29, CI[-2493.33, -392.65]). IV, 6-min walking test (6MWT) (40.82, CI[16.19, 64.92]) 3-min stair climb (3MSCT) (16.07, CI[12.16, 21.62]) increased elosulfase alfa at a dose 4.0 group. VI, recombinant human arylsulfatase B (rhASB) galsulfase (1.0 mg/kg/week) aggregation group (-217, CI[-258, -176]) (2.0 (-286.5, CI[-436.5, -136.5]), respectively. Moreover, most had high (34.8%) or unclear (43.5%) risk bias assessments assessment low. ERT alleviated symptoms some extent, but current evidence insufficient. Hence, further from large-sample RCT is needed.

Language: Английский

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Causes of death in mucopolysaccharidoses

Molecular Genetics and Metabolism, Journal Year: 2024, Volume and Issue: 142(3), P. 108507 - 108507

Published: May 24, 2024

Mucopolysaccharidoses are inherited metabolic diseases caused by mutations in genes encoding enzymes required for degradation of glycosaminoglycans. A lack or severe impairment activity these cause accumulation GAGs which is the primary biochemical defect. Depending on kind deficient enzyme, there 12 types and subtypes MPS distinguished. Despite common deficit (inefficient GAG degradation), course symptoms various can be different, though majority from group characterized significantly shortened live span. Here, we analysed frequency specific, direct causes death patients with different types, subject was not investigated comprehensively to date. We examined a total 1317 cases among patients, including 393 I, 418 II, 232 III, 45 IV, 208 VI, 22 VII. Our analyses indicated that most frequent differ between cardiovascular respiratory failures being predominant neurological deficits issues hydrops fetalis Results such studies suggest what specific clinical problems should considered highest priority apart attempts correct diseases, improve quality life prolong their lives.

Language: Английский

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