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Genetic and Metabolic Molecular Research of Lysosomal Storage Disease 2.0

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: closed (31 May 2022) | Viewed by 31631

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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
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Special Issue Information

Dear Colleagues,

Lysosomal storage diseases (LSD) 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 LSD 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 LSD created a breakthrough in treating genetic diseases, and several different therapeutic options are currently being studied, including hematopoietic stem cell transplantation, gene therapy, substrate reduction therapy, and others. However, to develop new therapies, the molecular mechanisms of LSD must be understood in great detail. Now is the time for extensive molecular research on LSD. This Special Issue is devoted to publishing the results of such studies, including basic research on the molecular mechanisms of LSD, 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 molecular aspects of various LSD.

Although the pathophysiology, mechanism, and therapeutic strategies of lysosomal storage diseases are topics covered by another Special Issue of IJMS, this issue is devoted to presenting research on the molecular aspects of these diseases. The Editors consider that this group of diseases is at the forefront of genetic and metabolic disorders that are studied on the molecular level, and our understanding of molecular mechanisms, molecular pharmacology, and clinical aspects on the molecular level is crucial for further research in this field, as well as for opening new ways of thinking about other, currently 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 (8 papers)

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Research

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15 pages, 3233 KiB  
Article
Gene Expression Analysis in gla-Mutant Zebrafish Reveals Enhanced Ca2+ Signaling Similar to Fabry Disease
by Hassan Osman Alhassan Elsaid, Håkon Tjeldnes, Mariell Rivedal, Camille Serre, Øystein Eikrem, Einar Svarstad, Camilla Tøndel, Hans-Peter Marti, Jessica Furriol and Janka Babickova
Int. J. Mol. Sci. 2023, 24(1), 358; https://doi.org/10.3390/ijms24010358 - 26 Dec 2022
Cited by 1 | Viewed by 1790
Abstract
Fabry disease (FD) is an X-linked inborn metabolic disorder due to partial or complete lysosomal α-galactosidase A deficiency. FD is characterized by progressive renal insufficiency and cardio- and cerebrovascular involvement. Restricted access on Gb3-independent tissue injury experimental models has limited the understanding of [...] Read more.
Fabry disease (FD) is an X-linked inborn metabolic disorder due to partial or complete lysosomal α-galactosidase A deficiency. FD is characterized by progressive renal insufficiency and cardio- and cerebrovascular involvement. Restricted access on Gb3-independent tissue injury experimental models has limited the understanding of FD pathophysiology and delayed the development of new therapies. Accumulating glycosphingolipids, mainly Gb3 and lysoGb3, are Fabry specific markers used in clinical follow up. However, recent studies suggest there is a need for additional markers to monitor FD clinical course or response to treatment. We used a gla-knockout zebrafish (ZF) to investigate alternative biomarkers in Gb3-free-conditions. RNA sequencing was used to identify transcriptomic signatures in kidney tissues discriminating gla-mutant (M) from wild type (WT) ZF. Gene Ontology (GO) and KEGG pathways analysis showed upregulation of immune system activation and downregulation of oxidative phosphorylation pathways in kidneys from M ZF. In addition, upregulation of the Ca2+ signaling pathway was also detectable in M ZF kidneys. Importantly, disruption of mitochondrial and lysosome-related pathways observed in M ZF was validated by immunohistochemistry. Thus, this ZF model expands the pathophysiological understanding of FD, the Gb3-independent effects of gla mutations could be used to explore new therapeutic targets for FD. Full article
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23 pages, 1899 KiB  
Article
Isogenic GAA-KO Murine Muscle Cell Lines Mimicking Severe Pompe Mutations as Preclinical Models for the Screening of Potential Gene Therapy Strategies
by Araceli Aguilar-González, Juan Elías González-Correa, Eliana Barriocanal-Casado, Iris Ramos-Hernández, Miguel A. Lerma-Juárez, Sara Greco, Juan José Rodríguez-Sevilla, Francisco Javier Molina-Estévez, Valle Montalvo-Romeral, Giuseppe Ronzitti, Rosario María Sánchez-Martín, Francisco Martín and Pilar Muñoz
Int. J. Mol. Sci. 2022, 23(11), 6298; https://doi.org/10.3390/ijms23116298 - 04 Jun 2022
Cited by 1 | Viewed by 3024
Abstract
Pompe disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the uptake of the GAA enzyme secreted by corrected cells. In the present study, [...] Read more.
Pompe disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the uptake of the GAA enzyme secreted by corrected cells. In the present study, we generated isogenic murine GAA-KO cell lines resembling severe mutations from Pompe patients. All of the generated GAA-KO cells lacked GAA activity and presented an increased autophagy and increased glycogen content by means of myotube differentiation as well as the downregulation of mannose 6-phosphate receptors (CI-MPRs), validating them as models for PD. Additionally, different chimeric murine GAA proteins (IFG, IFLG and 2G) were designed with the aim to improve their therapeutic activity. Phenotypic rescue analyses using lentiviral vectors point to IFG chimera as the best candidate in restoring GAA activity, normalising the autophagic marker p62 and surface levels of CI-MPRs. Interestingly, in vivo administration of liver-directed AAVs expressing the chimeras further confirmed the good behaviour of IFG, achieving cross-correction in heart tissue. In summary, we generated different isogenic murine muscle cell lines mimicking the severe PD phenotype, as well as validating their applicability as preclinical models in order to reduce animal experimentation. Full article
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15 pages, 3323 KiB  
Article
Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data
by Roberto Giugliani, Ana Maria Martins, Torayuki Okuyama, Yoshikatsu Eto, Norio Sakai, Kimitoshi Nakamura, Hideto Morimoto, Kohtaro Minami, Tatsuyoshi Yamamoto, Mariko Yamaoka, Toshiaki Ikeda, Sairei So, Kazunori Tanizawa, Hiroyuki Sonoda, Mathias Schmidt and Yuji Sato
Int. J. Mol. Sci. 2021, 22(20), 10938; https://doi.org/10.3390/ijms222010938 - 10 Oct 2021
Cited by 19 | Viewed by 3996
Abstract
Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts [...] Read more.
Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II. Full article
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16 pages, 7558 KiB  
Article
Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth
by Katharina B. Kuentzel, Ivan Bradić, Alena Akhmetshina, Melanie Korbelius, Silvia Rainer, Dagmar Kolb, Martin Gauster, Nemanja Vujić and Dagmar Kratky
Int. J. Mol. Sci. 2021, 22(19), 10416; https://doi.org/10.3390/ijms221910416 - 27 Sep 2021
Cited by 9 | Viewed by 2352
Abstract
Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity [...] Read more.
Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency. Full article
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11 pages, 1209 KiB  
Article
Design and Validation of a Custom NGS Panel Targeting a Set of Lysosomal Storage Diseases Candidate for NBS Applications
by Valentina La Cognata, Maria Guarnaccia, Giovanna Morello, Martino Ruggieri, Agata Polizzi and Sebastiano Cavallaro
Int. J. Mol. Sci. 2021, 22(18), 10064; https://doi.org/10.3390/ijms221810064 - 17 Sep 2021
Cited by 11 | Viewed by 3000
Abstract
Lysosomal storage diseases (LSDs) are a heterogeneous group of approximately 70 monogenic metabolic disorders whose diagnosis represents an arduous challenge for clinicians due to their variability in phenotype penetrance, clinical manifestations, and high allelic heterogeneity. In recent years, the approval of disease-specific therapies [...] Read more.
Lysosomal storage diseases (LSDs) are a heterogeneous group of approximately 70 monogenic metabolic disorders whose diagnosis represents an arduous challenge for clinicians due to their variability in phenotype penetrance, clinical manifestations, and high allelic heterogeneity. In recent years, the approval of disease-specific therapies and the rapid emergence of novel rapid diagnostic methods has opened, for a set of selected LSDs, the possibility for inclusion in extensive national newborn screening (NBS) programs. Herein, we evaluated the clinical utility and diagnostic validity of a targeted next-generation sequencing (tNGS) panel (called NBS_LSDs), designed ad hoc to scan the coding regions of six genes (GBA, GAA, SMPD1, IDUA1, GLA, GALC) relevant for a group of LSDs candidate for inclusion in national NBS programs (MPSI, Pompe, Fabry, Krabbe, Niemann Pick A-B and Gaucher diseases). A standard group of 15 samples with previously known genetic mutations was used to test and validate the entire flowchart. Analytical accuracy, sensitivity, and specificity, as well as turnaround time and costs, were assessed. Results showed that the Ion AmpliSeq and Ion Chef System-based high-throughput NBS_LSDs tNGS panel is a fast, accurate, and cost-effective process. The introduction of this technology into routine NBS procedures as a second-tier test along with primary biochemical assays will allow facilitating the identification and management of selected LSDs and reducing diagnostic delay. Full article
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19 pages, 3200 KiB  
Article
Investigating Immune Responses to the scAAV9-HEXM Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models
by Shalini Kot, Subha Karumuthil-Melethil, Evan Woodley, Violeta Zaric, Patrick Thompson, Zhilin Chen, Erik Lykken, John G. Keimel, William F. Kaemmerer, Steven J. Gray and Jagdeep S. Walia
Int. J. Mol. Sci. 2021, 22(13), 6751; https://doi.org/10.3390/ijms22136751 - 23 Jun 2021
Cited by 7 | Viewed by 4046
Abstract
GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. [...] Read more.
GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Viral vector gene transfer is viewed as a potential method of treating these diseases. A recently constructed isoenzyme to HexA, called HexM, has the ability to effectively catabolize GM2 gangliosides in vivo. Previous gene transfer studies have revealed that the scAAV9-HEXM treatment can improve survival in the murine SD model. However, it is speculated that this treatment could elicit an immune response to the carrier capsid and “non-self”-expressed transgene. This study was designed to assess the immunocompetence of TSD and SD mice, and test the immune response to the scAAV9-HEXM gene transfer. HexM vector-treated mice developed a significant anti-HexM T cell response and antibody response. This study confirms that TSD and SD mouse models are immunocompetent, and that gene transfer expression can create an immune response in these mice. These mouse models could be utilized for investigating methods of mitigating immune responses to gene transfer-expressed “non-self” proteins, and potentially improve treatment efficacy. Full article
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27 pages, 1917 KiB  
Review
Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism
by Bernadette Breiden and Konrad Sandhoff
Int. J. Mol. Sci. 2021, 22(16), 9001; https://doi.org/10.3390/ijms22169001 - 20 Aug 2021
Cited by 22 | Viewed by 5070
Abstract
Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we [...] Read more.
Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed. Full article
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36 pages, 3229 KiB  
Review
Fabry Disease and the Heart: A Comprehensive Review
by Olga Azevedo, Filipa Cordeiro, Miguel Fernandes Gago, Gabriel Miltenberger-Miltenyi, Catarina Ferreira, Nuno Sousa and Damião Cunha
Int. J. Mol. Sci. 2021, 22(9), 4434; https://doi.org/10.3390/ijms22094434 - 23 Apr 2021
Cited by 35 | Viewed by 6780
Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the [...] Read more.
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the body. GB3 accumulation occurs in virtually all cardiac cells (cardiomyocytes, conduction system cells, fibroblasts, and endothelial and smooth muscle vascular cells), ultimately leading to ventricular hypertrophy and fibrosis, heart failure, valve disease, angina, dysrhythmias, cardiac conduction abnormalities, and sudden death. Despite available therapies and supportive treatment, cardiac involvement carries a major prognostic impact, representing the main cause of death in FD. In the last years, knowledge has substantially evolved on the pathophysiological mechanisms leading to cardiac damage, the natural history of cardiac manifestations, the late-onset phenotypes with predominant cardiac involvement, the early markers of cardiac damage, the role of multimodality cardiac imaging on the diagnosis, management and follow-up of Fabry patients, and the cardiac efficacy of available therapies. Herein, we provide a comprehensive and integrated review on the cardiac involvement of FD, at the pathophysiological, anatomopathological, laboratory, imaging, and clinical levels, as well as on the diagnosis and management of cardiac manifestations, their supportive treatment, and the cardiac efficacy of specific therapies, such as enzyme replacement therapy and migalastat. Full article
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