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New Trends in Personalized Therapy of Thalassemia
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New Trends in Personalized Therapy of Thalassemia

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (31 August 2019)

Special Issue Editors

Prof. Dr. Roberto Gambari

E-Mail Website
Guest Editor
Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, Ferrara, Italy
Interests: OMICS analyses; transcriptional regulation of globin genes; gene therapy; induction of fetal hemoglobin, microRNAs, molecular diagnosis
Special Issues, Collections and Topics in MDPI journals
Dr. Eitan Fibach

E-Mail Website
Guest Editor
Dept. of Hematology, Hadassah - Hebrew University Medical Center, Ein-Kerem, Jerusalem, Israel
Interests: gene therapy; induction of fetal hemoglobin; in vitro experimental model systems; molecular diagnosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In beta−thalassemias, mutations of the beta-globin gene or its regulatory regions cause the absence or reduced synthesis of beta-globin chains. The disease is associated with morbidity and mortality due to severe chronic anemia or treatment-related complications. In the last years novel promising strategies have been developed for implementing therapeutic and diagnostic protocols regarding beta-thalassemia and related diseases (such as sickle cell anemia).

For instance, the first trials on gene therapy have been recently reported, based on the use of new generation of lentiviral vectors; induction of fetal hemoglobin using hydroxyurea is now firmly established as a strategy to ameliorate the clinical parameters of beta-thalassemia patients. These achievements are based on the development of in vitro and in vivo experimental systems, on the design on novel drugs (including DNA-based molecules) and suitable delivery systems for personalized therapy. Future developments are expected in the field of stem cell therapy, including induced pluripotent stem cells (iPS) derived from thalassemia patients. Diagnostic approaches are expected to bring important achievements in the field of non-invasive prenatal diagnosis.

We are particularly interested in review and research manuscripts that report the relevance of novel approaches for gene therapy, gene editing and improved diagnosis, prognosis and management of beta-thalassemias. Reviews that summarize the results of clinical trials are welcome as well. Moreover, papers dealing with methodological achievements leading to the development of novel therapeutic and diagnostic protocols facilitating personalized therapy in precision medicine would be of great interest.

Main topics include, but are not limited to:

  • Patients stratification
  • OMICS analyses
  • Transcriptional regulation of globin genes
  • Gene therapy for thalassemia
  • Gene editing
  • Read-through approaches for stop-codon mutations
  • Induction of Fetal Hemoglobin
  • Fetal globin modifiers
  • Stem cells
  • Development of iPS
  • MicroRNAs
  • Long non-coding RNAs
  • In vitro experimental model systems
  • In vivo experimental model systems, including transgenic animals
  • Molecular diagnosis
  • Prenatal diagnosis

Dr. Roberto Gambari
Dr. Eitan Fibach
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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • Thalassemia
  • Theranostics
  • Patients stratification
  • OMICS
  • Transcriptional regulation
  • Gene therapy
  • Gene editing
  • Read-through approaches
  • Induction of Fetal Hemoglobin
  • MicroRNAs
  • Prenatal diagnosis
  • Transgenic animals

Published Papers (5 papers)

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Research

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14 pages, 1761 KiB  
Communication
Proteomic Studies for the Investigation of γ-Globin Induction by Decitabine in Human Primary Erythroid Progenitor Cultures
by Andria Theodorou, Marios Phylactides, Eleni Katsantoni, Kostas Vougas, Spyros D. Garbis, Pavlos Fanis, Maria Sitarou, Swee Lay Thein and Marina Kleanthous
J. Clin. Med. 2020, 9(1), 134; https://doi.org/10.3390/jcm9010134 - 03 Jan 2020
Cited by 3 | Viewed by 3328
Abstract
Reactivation of γ-globin is considered a promising approach for the treatment of β-thalassemia and sickle cell disease. Therapeutic induction of γ-globin expression, however, is fraught with lack of suitable therapeutic targets. The aim of this study was to investigate the effects that treatment [...] Read more.
Reactivation of γ-globin is considered a promising approach for the treatment of β-thalassemia and sickle cell disease. Therapeutic induction of γ-globin expression, however, is fraught with lack of suitable therapeutic targets. The aim of this study was to investigate the effects that treatment with decitabine has on the proteome of human primary erythroid cells from healthy and thalassemic volunteers, as a means of identifying new potential pharmacological targets. Decitabine is a known γ-globin inducer, which is not, however, safe enough for clinical use. A proteomic approach utilizing isobaric tags for relative and absolute quantitation (iTRAQ) analysis, in combination with high-pH reverse phase peptide fractionation followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), was employed to investigate the effects of decitabine treatment. Bioinformatics analysis making use of the Database for Annotation, Visualization and Integrated Discovery (DAVID) was employed for functional annotation of the 192 differentially expressed proteins identified. The data are available via ProteomeXchange with identifier PXD006889. The proteins fall into various biological pathways, such as the NF-κB signaling pathway, and into many functional categories including regulation of cell proliferation, transcription factor and DNA binding, protein stabilization, chromatin modification and organization, and oxidative stress proteins. Full article
(This article belongs to the Special Issue New Trends in Personalized Therapy of Thalassemia)
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18 pages, 2626 KiB  
Article
The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements
by Petros Patsali, Claudio Mussolino, Petros Ladas, Argyro Floga, Annita Kolnagou, Soteroula Christou, Maria Sitarou, Michael N. Antoniou, Toni Cathomen, Carsten Werner Lederer and Marina Kleanthous
J. Clin. Med. 2019, 8(11), 1959; https://doi.org/10.3390/jcm8111959 - 13 Nov 2019
Cited by 11 | Viewed by 3321
Abstract
The common IVSI-110 (G>A) β-thalassemia mutation is a paradigm for intronic disease-causing mutations and their functional repair by non-homologous end joining-mediated disruption. Such mutation-specific repair by disruption of aberrant regulatory elements (DARE) is highly efficient, but to date, no systematic analysis has been [...] Read more.
The common IVSI-110 (G>A) β-thalassemia mutation is a paradigm for intronic disease-causing mutations and their functional repair by non-homologous end joining-mediated disruption. Such mutation-specific repair by disruption of aberrant regulatory elements (DARE) is highly efficient, but to date, no systematic analysis has been performed to evaluate disease-causing mutations as therapeutic targets. Here, DARE was performed in highly characterized erythroid IVSI-110(G>A) transgenic cells and the disruption events were compared with published observations in primary CD34+ cells. DARE achieved the functional correction of β-globin expression equally through the removal of causative mutations and through the removal of context sequences, with disruption events and the restriction of indel events close to the cut site closely resembling those seen in primary cells. Correlation of DNA-, RNA-, and protein-level findings then allowed the extrapolation of findings to other mutations by in silico analyses for potential repair based on the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9, Cas12a, and transcription activator-like effector nuclease (TALEN) platforms. The high efficiency of DARE and unexpected freedom of target design render the approach potentially suitable for 14 known thalassemia mutations besides IVSI-110(G>A) and put it forward for several prominent mutations causing other inherited diseases. The application of DARE, therefore, has a wide scope for sustainable personalized advanced therapy medicinal product development for thalassemia and beyond. Full article
(This article belongs to the Special Issue New Trends in Personalized Therapy of Thalassemia)
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25 pages, 4359 KiB  
Article
Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies
by Coralea Stephanou, Stella Tamana, Anna Minaidou, Panayiota Papasavva, Marina Kleanthous and Petros Kountouris
J. Clin. Med. 2019, 8(11), 1927; https://doi.org/10.3390/jcm8111927 - 09 Nov 2019
Cited by 10 | Viewed by 3943
Abstract
Haemoglobinopathies are common monogenic disorders with diverse clinical manifestations, partly attributed to the influence of modifier genes. Recent years have seen enormous growth in the amount of genetic data, instigating the need for ranking methods to identify candidate genes with strong modifying effects. [...] Read more.
Haemoglobinopathies are common monogenic disorders with diverse clinical manifestations, partly attributed to the influence of modifier genes. Recent years have seen enormous growth in the amount of genetic data, instigating the need for ranking methods to identify candidate genes with strong modifying effects. Here, we present the first evidence-based gene ranking metric (IthaScore) for haemoglobinopathy-specific phenotypes by utilising curated data in the IthaGenes database. IthaScore successfully reflects current knowledge for well-established disease modifiers, while it can be dynamically updated with emerging evidence. Protein–protein interaction (PPI) network analysis and functional enrichment analysis were employed to identify new potential disease modifiers and to evaluate the biological profiles of selected phenotypes. The most relevant gene ontology (GO) and pathway gene annotations for (a) haemoglobin (Hb) F levels/Hb F response to hydroxyurea included urea cycle, arginine metabolism and vascular endothelial growth factor receptor (VEGFR) signalling, (b) response to iron chelators included xenobiotic metabolism and glucuronidation, and (c) stroke included cytokine signalling and inflammatory reactions. Our findings demonstrate the capacity of IthaGenes, together with dynamic gene ranking, to expand knowledge on the genetic and molecular basis of phenotypic variation in haemoglobinopathies and to identify additional candidate genes to potentially inform and improve diagnosis, prognosis and therapeutic management. Full article
(This article belongs to the Special Issue New Trends in Personalized Therapy of Thalassemia)
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Review

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21 pages, 1985 KiB  
Review
Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia
by Monica Borgatti, Emiliano Altamura, Francesca Salvatori, Elisabetta D’Aversa and Nicola Altamura
J. Clin. Med. 2020, 9(2), 289; https://doi.org/10.3390/jcm9020289 - 21 Jan 2020
Cited by 20 | Viewed by 5043
Abstract
Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature [...] Read more.
Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature translation termination by inducing readthrough (or nonsense suppression) at the premature termination codon. These findings have introduced new hopes for the development of a pharmacologic approach to cure this genetic disease. In the present review, we first summarize the principle and current status of the chemical relief for the expression of functional proteins from genes otherwise unfruitful for the presence of nonsense mutations. Second, we compare data available on readthrough molecules for β0-thalassemia. The examples reported in the review strongly suggest that ribosomal readthrough should be considered as a therapeutic approach for the treatment of β0-thalassemia caused by nonsense mutations. Concluding, the discovery of molecules, exhibiting the property of inducing β-globin, such as readthrough compounds, is of great interest and represents a hope for several patients, whose survival will depend on the possible use of drugs rendering blood transfusion and chelation therapy unnecessary. Full article
(This article belongs to the Special Issue New Trends in Personalized Therapy of Thalassemia)
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15 pages, 297 KiB  
Review
Erythropoiesis In Vitro—A Research and Therapeutic Tool in Thalassemia
by Eitan Fibach
J. Clin. Med. 2019, 8(12), 2124; https://doi.org/10.3390/jcm8122124 - 02 Dec 2019
Cited by 9 | Viewed by 3921
Abstract
Thalassemia (thal) is a hereditary chronic hemolytic anemia due to a partial or complete deficiency in the production of globin chains, in most cases, α or β, which compose, together with the iron-containing porphyrins (hemes), the hemoglobin molecules in red blood cells (RBC). [...] Read more.
Thalassemia (thal) is a hereditary chronic hemolytic anemia due to a partial or complete deficiency in the production of globin chains, in most cases, α or β, which compose, together with the iron-containing porphyrins (hemes), the hemoglobin molecules in red blood cells (RBC). The major clinical symptom of β-thal is severe chronic anemia—a decrease in RBC number and their hemoglobin content. In spite of the improvement in therapy, thal still severely affects the quality of life of the patients and their families and imposes a substantial financial burden on the community. These considerations position β-thal, among other hemoglobinopathies, as a major health and social problem that deserves increased efforts in research and its clinical application. These efforts are based on clinical studies, experiments in animal models and the use of erythroid cells grown in culture. The latter include immortal cell lines and cultures initiated by erythroid progenitor and stem cells derived from the blood and RBC producing (erythropoietic) sites of normal and thal donors, embryonic stem cells, and recently, "induced pluripotent stem cells" generated by manipulation of differentiated somatic cells. The present review summarizes the use of erythroid cultures, their technological aspects and their contribution to the research and its clinical application in thal. The former includes deciphering of the normal and pathological biology of the erythroid cell development, and the latter—their role in developing innovative therapeutics—drugs and methods of gene therapy, as well as providing an alternative source of RBC that may complement or substitute blood transfusions. Full article
(This article belongs to the Special Issue New Trends in Personalized Therapy of Thalassemia)
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