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Genetic and Metabolic Molecular Research of Lysosomal Storage Disease: 5th Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 2666

Special Issue Editor

Prof. Dr. Grzegorz Wegrzyn

E-Mail Website
Guest Editor
Department of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland
Interests: gene expression regulation; DNA replication; bacteriophages; plasmids; human genetic diseases; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders in which the defects of various lysosomal enzymes and regulatory proteins result in the accumulation of different macromolecules in these organelles. Over 50 LSDs are described in the literature, and they are among the most intensively studied genetic disorders. They are also model genetic diseases for the development of various therapeutic approaches. The introduction of enzyme replacement therapy for LSDs created a breakthrough in treating genetic diseases, and several different therapeutic options are currently being studied, including hematopoietic stem cell transplantation, gene therapy, and substrate reduction therapy. However, to develop new therapies, the molecular mechanisms of LSDs must be understood in great detail. Now is the time for extensive molecular research on LSDs. This Special Issue is devoted to publishing the results of such studies, including basic research on the molecular mechanisms of LSDs, translational studies on novel therapies, and clinical investigations performed at the molecular level. Review articles on all these aspects are also welcome. Therefore, this Special Issue shall provide a comprehensive view on the molecular aspects of various LSDs.

This Issue is devoted to presenting research on the molecular aspects of lysosomal storage diseases. This group of diseases is at the forefront of genetic and metabolic disorders that are studied at the molecular level, and our understanding of molecular mechanisms, molecular pharmacology, and clinical aspects at the molecular level is crucial for further research in this field, as well as opening new ways of thinking about other less-understood diseases.

Prof. Dr. Grzegorz Wegrzyn
Guest Editor

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Keywords

  • lysosomal storage diseases
  • molecular mechanisms of genetic disorders metabolic diseases
  • accumulation of macromolecules in cells
  • enzyme replacement therapy
  • hematopoietic stem cell transplantation gene therapy
  • substrate reduction therapy
  • translational research
  • novel therapies for genetic diseases

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Published Papers (4 papers)

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Research

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22 pages, 9103 KB  
Article
Development of Small-Molecule Allosteric Modulators of Beta-Galactosidase (β-Gal) for the Treatment of GM1 Gangliosidosis and Morquio B
by Natàlia Pérez-Carmona, Elena Cubero, Ana Ruano, Maria Pons-Vizcarra, Aida Delgado, Ana Trapero, Marc Reves, Laura Rodríguez-Pascau, Joanne Taylor, Marc Martinell, Xavier Barril and Ana María García-Collazo
Int. J. Mol. Sci. 2026, 27(8), 3631; https://doi.org/10.3390/ijms27083631 - 18 Apr 2026
Viewed by 434
Abstract
GM1 gangliosidosis and Morquio B are rare lysosomal storage disorders (LSDs) with significant unmet medical needs. These disorders result from mutations in the galactosidase beta 1 (GLB1) gene, leading to impaired β-galactosidase (β-Gal) activity and toxic substrate accumulation. The lack of [...] Read more.
GM1 gangliosidosis and Morquio B are rare lysosomal storage disorders (LSDs) with significant unmet medical needs. These disorders result from mutations in the galactosidase beta 1 (GLB1) gene, leading to impaired β-galactosidase (β-Gal) activity and toxic substrate accumulation. The lack of approved disease-modifying therapies for GM1 gangliosidosis and Morquio B, along with the challenges of achieving effective central nervous system delivery, has driven interest in small-molecule pharmacological chaperones (PCs) to restore β-Gal stability and function. Using Gain Therapeutics’ Magellan™ platform, a novel allosteric binding site on β-Gal was identified, enabling the discovery of a new class of Structurally Targeted Allosteric Regulators (STARs). Medicinal chemistry optimization produced a structurally unique STAR compound series, demonstrating broad β-Gal stabilizing effects. The therapeutic potential of these compounds was evaluated in vitro using a canine fibroblast model of GM1 gangliosidosis, where they were shown to significantly reduce toxic GM1 ganglioside accumulation. Immunocytochemistry-based assays confirmed substrate clearance and provided reliable structure–activity relationships, guiding further compound development. Notably, STARs achieved greater substrate clearance than the competitive PC N-nonyl-deoxygalactonojirimycin (NN-DGJ) under the conditions tested, as demonstrated by immunocytochemistry-based assays. While these findings are encouraging, further in vivo studies are required to validate the therapeutic efficacy of these few STAR compounds, particularly in addressing the neurodegenerative aspects of GM1 gangliosidosis. This study underscores the potential of the Magellan platform in identifying STAR molecules and provides a strong foundation for further optimization and preclinical validation in GLB1-related disorders, particularly GM1 gangliosidosis. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease: 5th Edition)
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25 pages, 3639 KB  
Article
AAV Gene Therapy for MPS IVA with Induction of Immune Tolerance via Oral Administration of Epitope Peptides of N-Acetylgalactosamine-6-sulfate Sulfatase
by Sampurna Saikia, Yasuhiko Ago, Fnu Nidhi, Shaukat Khan, Zhengyu Ma and Shunji Tomatsu
Int. J. Mol. Sci. 2026, 27(5), 2278; https://doi.org/10.3390/ijms27052278 - 28 Feb 2026
Viewed by 478
Abstract
Mucopolysaccharidosis IVA (MPS IVA) is caused by the accumulation of undegraded glycosaminoglycans due to the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. MPS IVA manifests as progressive systemic skeletal dysplasia. Gene therapy (GT) is potentially a one-time treatment in which the enzyme is [...] Read more.
Mucopolysaccharidosis IVA (MPS IVA) is caused by the accumulation of undegraded glycosaminoglycans due to the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. MPS IVA manifests as progressive systemic skeletal dysplasia. Gene therapy (GT) is potentially a one-time treatment in which the enzyme is continuously produced, circulated, and delivered to target tissues. However, immune responses to gene products can diminish therapeutic efficacy. We hypothesized that oral delivery of tolerogenic peptides induces immune tolerance to human GALNS (hGALNS) in MPS IVA mice, enhancing therapeutic efficacy. Neonatal mice deficient in mouse GALNS (mGALNS) were treated orally with three T-cell/B-cell epitope peptides or hGALNS protein on alternate days from day 3 after birth to day 20 before intravenous injection with AAV9 vectors encoding human GALNS on day 30. The results are encouraging, with anti-hGALNS antibodies undetectable in the plasma of orally administered peptide groups. hGALNS enzyme activities in plasma and tissues were higher in the orally treated groups than in the non-tolerized control group. Keratan sulfate levels in plasma, liver, and bone were normalized. Complete correction for heart vacuolization was achieved in peptide-treated groups, and partial correction for bone pathology was observed in all GT-treated groups. Overall, oral tolerance induction using immunodominant peptides promises to significantly enhance the efficacy of AAV-GT for MPS IVA. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease: 5th Edition)
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Review

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38 pages, 1030 KB  
Review
Pompe Disease: Pathogenesis, Molecular Mechanisms, Neurological Aspects, Diagnostics and Modern Therapeutic Approaches
by Alexandra Sharshakova, Alisa Fattakhova, Valeriya Solovyeva, Albert Sufianov, Galina Sufianova, Grigorii Kutovoi and Albert Rizvanov
Int. J. Mol. Sci. 2026, 27(8), 3703; https://doi.org/10.3390/ijms27083703 - 21 Apr 2026
Viewed by 199
Abstract
Pompe disease (PD) is a neuromuscular autosomal recessive disorder caused by mutation in the GAA gene, which encodes acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing glycogen to glucose. Deficiency of this enzyme leads to pathological accumulation of glycogen in almost all tissues [...] Read more.
Pompe disease (PD) is a neuromuscular autosomal recessive disorder caused by mutation in the GAA gene, which encodes acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing glycogen to glucose. Deficiency of this enzyme leads to pathological accumulation of glycogen in almost all tissues of the body, with the most pronounced effects in cardiac and skeletal muscle, as well as in the central nervous system. Two major clinical forms of PD are recognized: infantile-onset PD, characterized by almost complete absence of GAA activity and severe cardiomyopathy and neurological abnormalities, and late-onset PD, which primarily presents with impairment of respiratory and motor function. Since 2006, enzyme replacement therapy with recombinant GAA has been used to treat PD, improving survival and quality of life. However, this approach has several limitations: the need for lifelong infusions, the risk of immune responses, and the inability of the enzyme to cross the blood–brain barrier, which is particularly critical for infantile-onset PD. Consequently, alternative strategies are being developed, including gene therapy using adeno-associated virus vectors for GAA delivery to target tissues; these approaches are currently in phase I/II clinical trials. Transplantation of genetically modified hematopoietic stem cells also represents a promising therapeutic strategy, offering a single-intervention treatment with long-lasting effects. This review discusses the molecular mechanisms of PD, current and emerging disease models, and therapeutic approaches, which together open prospects for the development of potentially one-time curative treatments, despite persistent challenges such as immunogenicity and the need for long-term efficacy monitoring. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease: 5th Edition)
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13 pages, 766 KB  
Review
Newborn Screening in Fabry Disease
by Marta Olszewska, Krzysztof Schwermer and Krzysztof Pawlaczyk
Int. J. Mol. Sci. 2025, 26(24), 12125; https://doi.org/10.3390/ijms262412125 - 17 Dec 2025
Viewed by 1112
Abstract
Fabry disease (FD) is an X-linked genetic disease caused by deficient α galactosidase A activity, leading to a lysosomal storage disorder of globotriaosylceramide, causing organ damages. There are two most common clinical manifestations of the disease: classic FD with a typical onset of [...] Read more.
Fabry disease (FD) is an X-linked genetic disease caused by deficient α galactosidase A activity, leading to a lysosomal storage disorder of globotriaosylceramide, causing organ damages. There are two most common clinical manifestations of the disease: classic FD with a typical onset of symptoms in childhood in males, and later-onset variants which may include female heterozygotes. The highly heterogeneous and nonspecific nature of FD’s symptoms and limited physicians’ awareness result in a significant diagnostic and therapeutic delay. Even though the implementation of newborn screening (NBS) gives us an opportunity for early diagnosis and timely treatment, it has not yet been universally adopted. Over twenty pilot studies and screening programs worldwide have been published, showing that FD is more prevalent than previously estimated, exceeding 1 in 40,000 males, mainly due to the high incidence of variants of unknown significance (VUSs). They also raised controversies regarding the diagnostic methods, results interpretation, ethical issues, clinical approach, and economic burden. This review analyzes recent studies of NBS for FD; examines the screening methods, prevalence findings, and natural history data; and assesses the benefits and risks of NBS. We conclude with suggestions for the screening program design and research priorities to ensure that screening leads to improved health outcomes with acceptable costs and psychosocial impact. Full article
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease: 5th Edition)
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