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Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II)
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Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II)

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 January 2020) | Viewed by 63057

Special Issue Editors

Prof. Dr. Maria Vittoria Cubellis

E-Mail Website
Guest Editor
Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy
Interests: protein stability; bioinformatics; PMM2-CDG; Fabry disease; pharmacological chaperones
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Lidia Larizza

E-Mail Website
Guest Editor
Experimental Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy
Interests: rare disorders of chromatin regulators; Rubinstein-Taybi and related syndromes of the epigenetic machinery; chromosomal/genomic instability syndromes with cancer predisposition; imprinting disorders affecting growth; neurodevelopmental imprinting disorders; genomic disorders; MARK4 gene; c-kit gene
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A rare disease is any disease that affects a small percentage of the population. The quantification of “small” is variable, and represents an artificial border that will necessarily change with the diffusion of genetic screenings. More than 5000 rare diseases have been described. Non-sense mutations, deletions, and insertions abolish the function of the affected proteins, but mis-sense mutations have variable effects that go from complete inactivation to a mild reduction of activity. At present, more than 70,000 mis-sense mutations have been reported. Taken together, these findings imply that there are different genotypes and phenotypes for any given disease. Bare figures give a flavor of the great challenge represented by rare diseases in terms of both diagnosis and therapy.

We seek papers that look into rare diseases with a genetic, biochemical, or bioinformatic approach. Papers addressing specific pharmacological therapies for rare diseases are especially welcome.

Prof. Maria Vittoria Cubellis
Prof. Lidia Larizza
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • rare diseases
  • genetic diseases, inborn
  • diagnosis
  • mutations
  • epigenetics
  • drugs
  • molecular chaperones
  • drug repositioning
  • bioinformatics
  • integrated omics approaches
  • precision medicine

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Published Papers (13 papers)

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Research

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16 pages, 2549 KiB  
Article
Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery
by Marcello Carotti, Martina Scano, Irene Fancello, Isabelle Richard, Giovanni Risato, Mona Bensalah, Michela Soardi and Dorianna Sandonà
Int. J. Mol. Sci. 2020, 21(5), 1813; https://doi.org/10.3390/ijms21051813 - 06 Mar 2020
Cited by 6 | Viewed by 3181
Abstract
Sarcoglycanopathies are rare limb girdle muscular dystrophies, still incurable, even though symptomatic treatments may slow down the disease progression. Most of the disease-causing defects are missense mutations leading to a folding defective protein, promptly removed by the cell’s quality control, even if possibly [...] Read more.
Sarcoglycanopathies are rare limb girdle muscular dystrophies, still incurable, even though symptomatic treatments may slow down the disease progression. Most of the disease-causing defects are missense mutations leading to a folding defective protein, promptly removed by the cell’s quality control, even if possibly functional. Recently, we repurposed small molecules screened for cystic fibrosis as potential therapeutics in sarcoglycanopathy. Indeed, cystic fibrosis transmembrane regulator (CFTR) correctors successfully recovered the defective sarcoglycan-complex in vitro. Our aim was to test the combined administration of some CFTR correctors with C17, the most effective on sarcoglycans identified so far, and evaluate the stability of the rescued sarcoglycan-complex. We treated differentiated myogenic cells from both sarcoglycanopathy and healthy donors, evaluating the global rescue and the sarcolemma localization of the mutated protein, by biotinylation assays and western blot analyses. We observed the additive/synergistic action of some compounds, gathering the first ideas on possible mechanism/s of action. Our data also suggest that a defective α-sarcoglycan is competent for assembly into the complex that, if helped in cell traffic, can successfully reach the sarcolemma. In conclusion, our results strengthen the idea that CFTR correctors, acting probably as proteostasis modulators, have the potential to progress as therapeutics for sarcoglycanopathies caused by missense mutations. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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24 pages, 14607 KiB  
Article
Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis
by Hannes Glaß, Patrick Neumann, Arun Pal, Peter Reinhardt, Alexander Storch, Jared Sterneckert and Andreas Hermann
Int. J. Mol. Sci. 2020, 21(5), 1797; https://doi.org/10.3390/ijms21051797 - 05 Mar 2020
Cited by 11 | Viewed by 3187
Abstract
Chorea acanthocytosis (ChAc), an ultra-rare devastating neurodegenerative disease, is caused by mutations in the VPS13A gene, which encodes for the protein chorein. Affected patients suffer from chorea, orofacial dyskinesia, epilepsy, parkinsonism as well as peripheral neuropathy. Although medium spinal neurons of the striatum [...] Read more.
Chorea acanthocytosis (ChAc), an ultra-rare devastating neurodegenerative disease, is caused by mutations in the VPS13A gene, which encodes for the protein chorein. Affected patients suffer from chorea, orofacial dyskinesia, epilepsy, parkinsonism as well as peripheral neuropathy. Although medium spinal neurons of the striatum are mainly affected, other regions are impaired as well over the course of the disease. Animal studies as well as studies on human erythrocytes suggest Lyn-kinase inhibition as valuable novel opportunity to treat ChAc. In order to investigate the peripheral neuropathy aspect, we analyzed induced pluripotent stem cell derived midbrain/hindbrain cell cultures from ChAc patients in vitro. We observed dendritic microtubule fragmentation. Furthermore, by using in vitro live cell imaging, we found a reduction in the number of lysosomes and mitochondria, shortened mitochondria, an increase in retrograde transport and hyperpolarization as measured with the fluorescent probe JC-1. Deep phenotyping pointed towards a proximal axonal deterioration as the primary axonal disease phenotype. Interestingly, pharmacological interventions, which proved to be successful in different models of ChAc, were ineffective in treating the observed axonal phenotypes. Our data suggests that treatment of this multifaceted disease might be cell type and/or neuronal subtype specific, and thus necessitates precision medicine in this ultra-rare disease. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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12 pages, 4171 KiB  
Article
Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes
by Ana Latorre-Pellicer, Ángela Ascaso, Laura Trujillano, Marta Gil-Salvador, Maria Arnedo, Cristina Lucia-Campos, Rebeca Antoñanzas-Pérez, Iñigo Marcos-Alcalde, Ilaria Parenti, Gloria Bueno-Lozano, Antonio Musio, Beatriz Puisac, Frank J. Kaiser, Feliciano J. Ramos, Paulino Gómez-Puertas and Juan Pié
Int. J. Mol. Sci. 2020, 21(3), 1042; https://doi.org/10.3390/ijms21031042 - 04 Feb 2020
Cited by 40 | Viewed by 7903
Abstract
Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and [...] Read more.
Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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22 pages, 2105 KiB  
Article
Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease
by Jan Lukas, Chiara Cimmaruta, Ludovica Liguori, Supansa Pantoom, Katharina Iwanov, Janine Petters, Christina Hund, Maik Bunschkowski, Andreas Hermann, Maria Vittoria Cubellis and Arndt Rolfs
Int. J. Mol. Sci. 2020, 21(3), 956; https://doi.org/10.3390/ijms21030956 - 31 Jan 2020
Cited by 15 | Viewed by 4209
Abstract
Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal α-galactosidase A (α-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an [...] Read more.
Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal α-galactosidase A (α-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an alternative to intravenous enzyme replacement therapy. The decision as to whether a patient should be treated with DGJ depends on the genetic variant within the α-galactosidase A encoding gene (GLA). A good laboratory practice (GLP)-validated cell culture-based assay to investigate the biochemical responsiveness of the variants is currently the only source available to obtain pivotal information about susceptibility to treatment. Herein, variants were defined amenable when an absolute increase in enzyme activity of ≥3% of wild type enzyme activity and a relative increase in enzyme activity of ≥1.2-fold was achieved following DGJ treatment. Efficacy testing was carried out for over 1000 identified GLA variants in cell culture. Recent data suggest that about one-third of the variants comply with the amenability criteria. A recent study highlighted the impact of inter-assay variability on DGJ amenability, thereby reducing the power of the assay to predict eligible patients. This prompted us to compare our own α-galactosidase A enzyme activity data in a very similar in-house developed assay with those from the GLP assay. In an essentially retrospective approach, we reviewed 148 GLA gene variants from our former studies for which enzyme data from the GLP study were available and added novel data for 30 variants. We also present data for 18 GLA gene variants for which no data from the GLP assay are currently available. We found that both differences in experimental biochemical data and the criteria for the classification of amenability cause inter-assay discrepancy. We conclude that low baseline activity, borderline biochemical responsiveness, and inter-assay discrepancy are alarm signals for misclassifying a variant that must not be ignored. Furthermore, there is no solid basis for setting a minimum response threshold on which a clinical indication with DGJ can be justified. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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15 pages, 2788 KiB  
Article
β-Glucose-1,6-Bisphosphate Stabilizes Pathological Phophomannomutase2 Mutants In Vitro and Represents a Lead Compound to Develop Pharmacological Chaperones for the Most Common Disorder of Glycosylation, PMM2-CDG
by Maria Monticelli, Ludovica Liguori, Mariateresa Allocca, Giuseppina Andreotti and Maria Vittoria Cubellis
Int. J. Mol. Sci. 2019, 20(17), 4164; https://doi.org/10.3390/ijms20174164 - 26 Aug 2019
Cited by 28 | Viewed by 3661
Abstract
A large number of mutations causing PMM2-CDG, which is the most frequent disorder of glycosylation, destabilize phosphomannomutase2. We looked for a pharmacological chaperone to cure PMM2-CDG, starting from the structure of a natural ligand of phosphomannomutase2, α-glucose-1,6-bisphosphate. The compound, β-glucose-1,6-bisphosphate, was synthesized and [...] Read more.
A large number of mutations causing PMM2-CDG, which is the most frequent disorder of glycosylation, destabilize phosphomannomutase2. We looked for a pharmacological chaperone to cure PMM2-CDG, starting from the structure of a natural ligand of phosphomannomutase2, α-glucose-1,6-bisphosphate. The compound, β-glucose-1,6-bisphosphate, was synthesized and characterized via 31P-NMR. β-glucose-1,6-bisphosphate binds its target enzyme in silico. The binding induces a large conformational change that was predicted by the program PELE and validated in vitro by limited proteolysis. The ability of the compound to stabilize wild type phosphomannomutase2, as well as frequently encountered pathogenic mutants, was measured using thermal shift assay. β-glucose-1,6-bisphosphate is relatively resistant to the enzyme that specifically hydrolyses natural esose-bisphosphates. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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9 pages, 673 KiB  
Communication
Glucosylsphingosine (lyso-Gb1) as a Biomarker for Monitoring Treated and Untreated Children with Gaucher Disease
by Noa Hurvitz, Tama Dinur, Michal Becker-Cohen, Claudia Cozma, Marina Hovakimyan, Sebastian Oppermann, Laura Demuth, Arndt Rolfs, Aya Abramov, Ari Zimran and Shoshana Revel-Vilk
Int. J. Mol. Sci. 2019, 20(12), 3033; https://doi.org/10.3390/ijms20123033 - 21 Jun 2019
Cited by 48 | Viewed by 5403
Abstract
The role of glucosylsphingosine (lyso-Gb1), a downstream metabolic product of glucosylceramide, for monitoring treated and untreated children with Gaucher disease (GD) has not yet been studied. We reviewed the clinical charts of 81 children (<18 years), 35 with mild type 1 GD (GD1), [...] Read more.
The role of glucosylsphingosine (lyso-Gb1), a downstream metabolic product of glucosylceramide, for monitoring treated and untreated children with Gaucher disease (GD) has not yet been studied. We reviewed the clinical charts of 81 children (<18 years), 35 with mild type 1 GD (GD1), 34 with severe GD1 and 12 with type 3 GD (GD3), followed at Shaare Zedek Medical Center between 2014–2018. Disease severity for GD1 was based on genotypes. Forty children (87%) with severe GD1 and GD3 received enzyme replacement therapy (ERT) compared to two children (6%) with mild GD1. Lyso-Gb1 measurements were conducted on dried blood spot samples taken at each clinic visit. Lyso-Gb1 levels were significantly lower in children with mild compared to severe GD1 (p = 0.009). In untreated children, lyso-Gb1 levels were inversely correlated with platelet counts. During follow-up, lyso-Gb1 increased in almost 50% of untreated children, more commonly in younger children. In treated children, lyso-Gb1 levels were inversely correlated with hemoglobin levels. The increase of lyso-Gb1 while receiving ERT, seen in eight children, was partly associated with compliance and weight gain. Lyso-Gb1 seems to be a useful biomarker for monitoring children with GD and should be included in the routine follow-up. Progressive increase in lyso-Gb1 levels in untreated children suggests ERT initiation. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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8 pages, 793 KiB  
Communication
Chiari Malformation Type 1 in EPAS1-Associated Syndrome
by Jared S. Rosenblum, Dominic Maggio, Ying Pang, Matthew A. Nazari, Melissa K. Gonzales, Ronald M. Lechan, James G. Smirniotopoulos, Zhengping Zhuang, Karel Pacak and John D. Heiss
Int. J. Mol. Sci. 2019, 20(11), 2819; https://doi.org/10.3390/ijms20112819 - 10 Jun 2019
Cited by 8 | Viewed by 3771
Abstract
A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of EPAS1, encoding HIF-2α, was previously described. HIF-2α has been implicated in endochondral and intramembranous ossification. Abnormal bone growth of the skull base may lead to Chiari malformation [...] Read more.
A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of EPAS1, encoding HIF-2α, was previously described. HIF-2α has been implicated in endochondral and intramembranous ossification. Abnormal bone growth of the skull base may lead to Chiari malformation type I. We report two cases of EPAS1 gain-of-function mutation syndrome with Chiari malformation and developmental skull base anomalies. Patients were referred to the Section on Medical Endocrinology, Eunice Kennedy Shriver NICHD, NIH for evaluation of recurrent and metastatic paragangliomas or pheochromocytoma. The syndrome was confirmed genetically by identification of the functional EPAS1 gain-of-function mutation in the resected tumors and circulating leukocytes. Both patients were confirmed for characteristics of EPAS1 gain-of-function mutation syndrome by complete blood count (CBC), plasma biochemistry, and computed tomography (CT) of the abdomen and pelvis. Chiari malformation type I and abnormal bony development of the posterior fossa was found on MRI and CT of the head. The present study implicates EPAS1 mutations in abnormal posterior fossa development resulting in Chiari malformation type I. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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15 pages, 8317 KiB  
Article
Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles
by Laura Rigon, Marika Salvalaio, Francesca Pederzoli, Elisa Legnini, Jason Thomas Duskey, Francesca D’Avanzo, Concetta De Filippis, Barbara Ruozi, Oriano Marin, Maria Angela Vandelli, Ilaria Ottonelli, Maurizio Scarpa, Giovanni Tosi and Rosella Tomanin
Int. J. Mol. Sci. 2019, 20(8), 2014; https://doi.org/10.3390/ijms20082014 - 24 Apr 2019
Cited by 44 | Viewed by 3973
Abstract
Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. [...] Read more.
Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. The main treatment is represented by a weekly infusion of the functional enzyme, which cannot cross the blood-brain barrier and reach the central nervous system. In this study, a tailored nanomedicine approach based on brain-targeted polymeric nanoparticles (g7-NPs), loaded with the therapeutic enzyme, was exploited. Fibroblasts from MPSII patients were treated for 7 days with NPs loaded with the IDS enzyme; an induced IDS activity like the one detected in healthy cells was measured, together with a reduction of GAG content to non-pathological levels. An in vivo short-term study in MPSII mice was performed by weekly administration of g7-NPs-IDS. Biochemical, histological, and immunohistochemical evaluations of liver and brain were performed. The 6-weeks treatment produced a significant reduction of GAG deposits in liver and brain tissues, as well as a reduction of some neurological and inflammatory markers (i.e., LAMP2, CD68, GFAP), highlighting a general improvement of the brain pathology. The g7-NPs-IDS approach allowed a brain-targeted enzyme replacement therapy. Based on these positive results, the future aim will be to optimize NP formulation further to gain a higher efficacy of the proposed approach. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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Review

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51 pages, 1089 KiB  
Review
Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes
by Yuliya Markitantova and Vladimir Simirskii
Int. J. Mol. Sci. 2020, 21(5), 1602; https://doi.org/10.3390/ijms21051602 - 26 Feb 2020
Cited by 18 | Viewed by 7352
Abstract
Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption [...] Read more.
Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption of eye organogenesis and result in inherited eye/retinal diseases. Many of these diseases are part of the same clinical spectrum and have high genetic heterogeneity with already identified associated genes. We summarize the known key regulators of eye development, with a focus on the homeobox genes associated with monogenic eye diseases showing retinal manifestations. Recent advances in the field of genetics and high-throughput next-generation sequencing technologies, including single-cell transcriptome analysis have allowed for deepening of knowledge of the genetic basis of inherited retinal diseases (IRDs), as well as improve their diagnostics. We highlight some promising avenues of research involving molecular-genetic and cell-technology approaches that can be effective for IRDs therapy. The most promising neuroprotective strategies are aimed at mobilizing the endogenous cellular reserve of the retina. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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20 pages, 2631 KiB  
Review
Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations
by Ludovica Liguori, Maria Monticelli, Mariateresa Allocca, Bruno Hay Mele, Jan Lukas, Maria Vittoria Cubellis and Giuseppina Andreotti
Int. J. Mol. Sci. 2020, 21(2), 489; https://doi.org/10.3390/ijms21020489 - 13 Jan 2020
Cited by 66 | Viewed by 6507
Abstract
The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind [...] Read more.
The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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17 pages, 976 KiB  
Review
Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy
by Libero Vitiello, Lucia Tibaudo, Elena Pegoraro, Luca Bello and Marcella Canton
Int. J. Mol. Sci. 2019, 20(23), 6053; https://doi.org/10.3390/ijms20236053 - 30 Nov 2019
Cited by 13 | Viewed by 3877
Abstract
Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or [...] Read more.
Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s; recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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19 pages, 2917 KiB  
Review
An Overview of Circular RNAs and Their Implications in Myotonic Dystrophy
by Karol Czubak, Saam Sedehizadeh, Piotr Kozlowski and Marzena Wojciechowska
Int. J. Mol. Sci. 2019, 20(18), 4385; https://doi.org/10.3390/ijms20184385 - 06 Sep 2019
Cited by 14 | Viewed by 4254
Abstract
Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and post-transcriptionally via a back-splicing mechanism, requires the presence of complementary and/or inverted repeat sequences in introns flanking back-spliced exons and is facilitated by [...] Read more.
Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and post-transcriptionally via a back-splicing mechanism, requires the presence of complementary and/or inverted repeat sequences in introns flanking back-spliced exons and is facilitated by RNA-binding proteins. CircRNAs are abundant across eukaryotes; however, their biological functions remain largely speculative. Recently, they have been emerging as new members of a gene regulatory network and contributing factors in various human diseases including cancer, neurological, muscular and cardiovascular disorders. In this review, we present an overview of the current knowledge about circRNAs biogenesis and their aberrant expression in various human disorders. In particular, we focus on the latest discovery of circRNAs global upregulation in myotonic dystrophy type 1 (DM1) skeletal muscles and the role these prospective biomarkers might have for prognosis and therapeutic response in DM1. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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18 pages, 264 KiB  
Review
B Cells and Antibodies in Kawasaki Disease
by Michael E. Lindquist and Mark D. Hicar
Int. J. Mol. Sci. 2019, 20(8), 1834; https://doi.org/10.3390/ijms20081834 - 13 Apr 2019
Cited by 33 | Viewed by 4931
Abstract
The etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology supports a relationship of KD to an infectious disease. Several pathological mechanisms are being considered, including a superantigen response, direct invasion by an infectious [...] Read more.
The etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology supports a relationship of KD to an infectious disease. Several pathological mechanisms are being considered, including a superantigen response, direct invasion by an infectious etiology or an autoimmune phenomenon. Treating affected patients with intravenous immunoglobulin is effective at reducing the rates of coronary aneurysms. However, the role of B cells and antibodies in KD pathogenesis remains unclear. Murine models are not clear on the role for B cells and antibodies in pathogenesis. Studies on rare aneurysm specimens reveal plasma cell infiltrates. Antibodies generated from these aneurysmal plasma cell infiltrates showed cross-reaction to intracellular inclusions in the bronchial epithelium of a number of pathologic specimens from children with KD. These antibodies have not defined an etiology. Notably, a number of autoantibody responses have been reported in children with KD. Recent studies show acute B cell responses are similar in children with KD compared to children with infections, lending further support of an infectious disease cause of KD. Here, we will review and discuss the inconsistencies in the literature in relation to B cell responses, specific antibodies, and a potential role for humoral immunity in KD pathogenesis or diagnosis. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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