Special Issue "Gene Therapy"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 October 2016) | Viewed by 31371

Special Issue Editor

Dr. Michael A. Barry
E-Mail Website
Guest Editor
Department of Medicine, Mayo Clinic, Rochester, MN 55902, USA
Interests: gene-based vaccines; gene therapy; oncolytic virotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Many gene therapy and genetic vaccine vectors are non-replicating agents. If they deliver one transgene to the cell, they then express ³1X² of the transgene protein.  While replication-defective vectors can be potent, replication-competent vectors can surpass this potency by replicating transgenes in each cell to amplify therapeutic or vaccine responses.  In many cases, apples and oranges comparisons of replication-defective and replication-competent vectors are performed.  This issue will discuss vectors with and without replicating functions with particular emphasis on head to head comparisons of replication-defective, single-cycle, and replication-competent vectors.

Prof. Dr. Michael A. Barry
Guest Editor

Manuscript Submission Information

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Keywords

  • Replication-defective
  • Replication-competent
  • Single-cycle
  • Gene Therapy
  • Gene-based Vaccines
  • Cancer Gene Therapy
  • Cancer Vaccines
  • Cancer Immunotherapy

Published Papers (7 papers)

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Research

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Article
Transgene Expression and Host Cell Responses to Replication-Defective, Single-Cycle, and Replication-Competent Adenovirus Vectors
Genes 2017, 8(2), 79; https://doi.org/10.3390/genes8020079 - 18 Feb 2017
Cited by 11 | Viewed by 2727
Abstract
Most adenovirus (Ad) vectors are E1 gene deleted replication defective (RD-Ad) vectors that deliver one transgene to the cell and all expression is based on that one gene. In contrast, E1-intact replication-competent Ad (RC-Ad) vectors replicate their DNA and their transgenes up to [...] Read more.
Most adenovirus (Ad) vectors are E1 gene deleted replication defective (RD-Ad) vectors that deliver one transgene to the cell and all expression is based on that one gene. In contrast, E1-intact replication-competent Ad (RC-Ad) vectors replicate their DNA and their transgenes up to 10,000-fold, amplifying transgene expression markedly higher than RD-Ad vectors. While RC-Ad are more potent, they run the real risk of causing adenovirus infections in vector recipients and those that administer them. To gain the benefits of transgene amplification, but avoid the risk of Ad infections, we developed “single cycle” Ad (SC-Ad) vectors. SC-Ads amplify transgene expression and generated markedly stronger and more persistent immune responses than RD-Ad as expected. However, they also unexpectedly generated stronger immune responses than RC-Ad vectors. To explore the basis of this potency here, we compared gene expression and the cellular responses to infection to these vectors in vitro and in vivo. In vitro, in primary human lung epithelial cells, SC- and RC-Ad amplified their genomes more than 400-fold relative to RD-Ad with higher replication by SC-Ad. This replication translated into higher green fluorescent protein (GFP) expression for 48 h by SC- and RC-Ad than by RD-Ad. In vitro, in the absence of an immune system, RD-Ad expression became higher by 72 h coincident with cell death mediated by SC- and RC-Ad and release of transgene product from the dying cells. When the vectors were compared in human THP-1 Lucia- interferon-stimulated gene (ISG) cells, which are a human monocyte cell line that have been modified to quantify ISG activity, RC-Ad6 provoked significantly stronger ISG responses than RD- or SC-Ad. In mice, intravenous or intranasal injection produced up to 100-fold genome replication. Under these in vivo conditions in the presence of the immune system, luciferase expression by RC and SC-Ad was markedly higher than that by RD-Ad. In immunodeficient mice, SC-Ad drove stronger luciferase expression than RC- or RD-Ad. These data demonstrate better transgene expression by SC- and RC-Ad in vitro and in vivo than RD-Ad. This higher expression by the replicating vectors results in a peak of expression within 1 to 2 days followed by cell death of infected cells and release of transgene products. While SC- and RC-Ad expression were similar in mice and in Syrian hamsters, RC-Ad provoked much stronger ISG induction which may explain in part SC-Ad′s ability to generate stronger and more persistent immune responses than RC-Ad in Ad permissive hamsters. Full article
(This article belongs to the Special Issue Gene Therapy)
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Communication
Early Insights from Commercialization of Gene Therapies in Europe
Genes 2017, 8(2), 78; https://doi.org/10.3390/genes8020078 - 17 Feb 2017
Cited by 34 | Viewed by 2724
Abstract
After years of research and development, gene therapies are now becoming a commercial reality with several products approved by European regulatory authorities [...] Full article
(This article belongs to the Special Issue Gene Therapy)
Article
Magnetofection Enhances Lentiviral-Mediated Transduction of Airway Epithelial Cells through Extracellular and Cellular Barriers
Genes 2016, 7(11), 103; https://doi.org/10.3390/genes7110103 - 23 Nov 2016
Cited by 10 | Viewed by 2304
Abstract
Gene transfer to airway epithelial cells is hampered by extracellular (mainly mucus) and cellular (tight junctions) barriers. Magnetofection has been used to increase retention time of lentiviral vectors (LV) on the cellular surface. In this study, magnetofection was investigated in airway epithelial cell [...] Read more.
Gene transfer to airway epithelial cells is hampered by extracellular (mainly mucus) and cellular (tight junctions) barriers. Magnetofection has been used to increase retention time of lentiviral vectors (LV) on the cellular surface. In this study, magnetofection was investigated in airway epithelial cell models mimicking extracellular and cellular barriers. Bronchiolar epithelial cells (H441 line) were evaluated for LV-mediated transduction after polarization onto filters and dexamethasone (dex) treatment, which induced hemicyst formation, with or without magnetofection. Sputum from cystic fibrosis (CF) patients was overlaid onto cells, and LV-mediated transduction was evaluated in the absence or presence of magnetofection. Magnetofection of unpolarized H441 cells increased the transduction with 50 MOI (multiplicity of infection, i.e., transducing units/cell) up to the transduction obtained with 500 MOI in the absence of magnetofection. Magnetofection well-enhanced LV-mediated transduction in mucus-layered cells by 20.3-fold. LV-mediated transduction efficiency decreased in dex-induced hemicysts in a time-dependent fashion. In dome-forming cells, zonula occludens-1 (ZO-1) localization at the cell borders was increased by dex treatment. Under these experimental conditions, magnetofection significantly increased LV transduction by 5.3-fold. In conclusion, these results show that magnetofection can enhance LV-mediated gene transfer into airway epithelial cells in the presence of extracellular (sputum) and cellular (tight junctions) barriers, representing CF-like conditions. Full article
(This article belongs to the Special Issue Gene Therapy)
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Review

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Review
Historical and Clinical Experiences of Gene Therapy for Solid Cancers in China
Genes 2017, 8(3), 85; https://doi.org/10.3390/genes8030085 - 24 Feb 2017
Cited by 5 | Viewed by 3277
Abstract
Based on the theoretical and clinical development of modern medicines, gene therapy has been a promising treatment strategy for cancer and other diseases. The practice of gene therapy is nearly 27 years old, since the first authorized gene transfer study took place at [...] Read more.
Based on the theoretical and clinical development of modern medicines, gene therapy has been a promising treatment strategy for cancer and other diseases. The practice of gene therapy is nearly 27 years old, since the first authorized gene transfer study took place at the National Institute of Health in 1989. However, gene therapy was not readily adopted worldwide, until recently. Several gene therapy clinical trials have been carried out in China since 1998, and medical research in China has flourished. In this report, we review the history of gene therapy in China, focusing on treatment protocol, the administration cycle, dosage calculation, and the evaluation of therapeutic effects, in order to provide more information for the additional development of this promising treatment strategy. Full article
(This article belongs to the Special Issue Gene Therapy)
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Review
Advances in Non-Viral DNA Vectors for Gene Therapy
Genes 2017, 8(2), 65; https://doi.org/10.3390/genes8020065 - 10 Feb 2017
Cited by 193 | Viewed by 8515
Abstract
Uses of viral vectors have thus far eclipsed uses of non-viral vectors for gene therapy delivery in the clinic. Viral vectors, however, have certain issues involving genome integration, the inability to be delivered repeatedly, and possible host rejection. Fortunately, development of non-viral DNA [...] Read more.
Uses of viral vectors have thus far eclipsed uses of non-viral vectors for gene therapy delivery in the clinic. Viral vectors, however, have certain issues involving genome integration, the inability to be delivered repeatedly, and possible host rejection. Fortunately, development of non-viral DNA vectors has progressed steadily, especially in plasmid vector length reduction, now allowing these tools to fill in specifically where viral or other non-viral vectors may not be the best options. In this review, we examine the improvements made to non-viral DNA gene therapy vectors, highlight opportunities for their further development, address therapeutic needs for which their use is the logical choice, and discuss their future expansion into the clinic Full article
(This article belongs to the Special Issue Gene Therapy)
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Review
Targeting MicroRNAs in Cancer Gene Therapy
Genes 2017, 8(1), 21; https://doi.org/10.3390/genes8010021 - 09 Jan 2017
Cited by 119 | Viewed by 5278
Abstract
MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged [...] Read more.
MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer. Full article
(This article belongs to the Special Issue Gene Therapy)
Review
Gene Therapy: A Paradigm Shift in Dentistry
Genes 2016, 7(11), 98; https://doi.org/10.3390/genes7110098 - 10 Nov 2016
Cited by 13 | Viewed by 6130
Abstract
Gene therapy holds a promising future for bridging the gap between the disciplines of medicine and clinical dentistry. The dynamic treatment approaches of gene therapy have been advancing by leaps and bounds. They are transforming the conventional approaches into more precise and preventive [...] Read more.
Gene therapy holds a promising future for bridging the gap between the disciplines of medicine and clinical dentistry. The dynamic treatment approaches of gene therapy have been advancing by leaps and bounds. They are transforming the conventional approaches into more precise and preventive ones that may limit the need of using drugs and surgery. The oral cavity is one of the most accessible areas for the clinical applications of gene therapy for various oral tissues. The idea of genetic engineering has become more exciting due to its advantages over other treatment modalities. For instance, the body is neither subjected to an invasive surgery nor deep wounds, nor is it susceptible to systemic effects of drugs. The aim of this article is to review the gene therapy applications in the field of dentistry. In addition, therapeutic benefits in terms of treatment of diseases, minimal invasion and maximum outcomes have been discussed. Full article
(This article belongs to the Special Issue Gene Therapy)
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