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Gene Therapy
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Gene Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (20 September 2012) | Viewed by 57232

Special Issue Editor

Prof. Dr. Leonidas A. Phylactou

E-Mail Website
Guest Editor
Chief Executive Officer and Medical Director, The Cyprus Institute of Neurology & Genetics, PO Box 23462, Nicosia 1683, Cyprus
Interests: RNA biology; regulatory RNA molecules; extracellular vesicles; identification of genetic defects in inherited diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gene therapy is considered very promising for the therapy of several diseases, whether these are inherited or acquired during life. Although it is a field which has peaked relatively recently, the rationale behind all the gene therapy approaches are based on fundamental genetics and molecular biology, aiming at interfering at all stages of the flow of the genetic information. Currently, gene therapy protocols are developed for the delivery of genetic material with viral and non-viral methods, the down-regulation of gene expression at the DNA, RNA and protein levels (anti-gene, RNA interference, antisense, ribozymes, aptamers etc) and the expression of transgenes and genetic sequences. Gene therapy is now advanced against several common and rare diseases. For example, several approaches are being developed for the therapy of cancer, diabetes, cardiovascular diseases, infectious and inherited disorders. Some of these approaches are at the pre-clinical stage but some have progressed to clinical trials. Gene therapy is the way to treat several diseases in the future and research progress in this field has shown that this is achievable.

Dr. Leonidas A. Phylactou
Guest Editor

Keywords

  • gene therapy
  • viral vectors
  • non-viral vectors
  • antisense
  • RNA interference
  • ribozymes
  • aptamers
  • inducible expression
  • tissue-specific expression
  • genome modification

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Published Papers (6 papers)

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Research

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442 KiB  
Article
Physical Factors Affecting Plasmid DNA Compaction in Stearylamine-Containing Nanoemulsions Intended for Gene Delivery
by André Leandro Silva, Francisco Alexandrino, Júnior, Lourena Mafra Verissimo, Lucymara Fassarella Agnez-Lima, Lucila Carmem Monte Egito, Anselmo Gomes De Oliveira and Eryvaldo Socrates Tabosa Do Egito
Pharmaceuticals 2012, 5(6), 643-654; https://doi.org/10.3390/ph5060643 - 18 Jun 2012
Cited by 12 | Viewed by 7161
Abstract
Cationic lipids have been used in the development of non-viral gene delivery systems as lipoplexes. Stearylamine, a cationic lipid that presents a primary amine group when in solution, is able to compact genetic material by electrostatic interactions. In dispersed systems such as nanoemulsions [...] Read more.
Cationic lipids have been used in the development of non-viral gene delivery systems as lipoplexes. Stearylamine, a cationic lipid that presents a primary amine group when in solution, is able to compact genetic material by electrostatic interactions. In dispersed systems such as nanoemulsions this lipid anchors on the oil/water interface confering a positive charge to them. The aim of this work was to evaluate factors that influence DNA compaction in cationic nanoemulsions containing stearylamine. The influence of the stearylamine incorporation phase (water or oil), time of complexation, and different incubation temperatures were studied. The complexation rate was assessed by electrophoresis migration on agarose gel 0.7%, and nanoemulsion and lipoplex characterization was done by Dynamic Light Scattering (DLS). The results demonstrate that the best DNA compaction process occurs after 120 min of complexation, at low temperature (4 ± 1 °C), and after incorporation of the cationic lipid into the aqueous phase. Although the zeta potential of lipoplexes was lower than the results found for basic nanoemulsions, the granulometry did not change. Moreover, it was demonstrated that lipoplexes are suitable vehicles for gene delivery. Full article
(This article belongs to the Special Issue Gene Therapy)
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572 KiB  
Article
The Signalling Role of the avβ5-Integrin Can Impact the Efficacy of AAV in Retinal Gene Therapy
by Therese Cronin, Daniel C. Chung, Ying Yang, Emeline F. Nandrot and Jean Bennett
Pharmaceuticals 2012, 5(5), 447-459; https://doi.org/10.3390/ph5050447 - 2 May 2012
Cited by 5 | Viewed by 6926
Abstract
Sub-retinal injection of the common AAV2 pseudotypes frequently results in strong transduction of the retinal pigment epithelium (RPE) as well as the retina itself. This has been of benefit to date in human clinical trials using AAV, where the disease target is in [...] Read more.
Sub-retinal injection of the common AAV2 pseudotypes frequently results in strong transduction of the retinal pigment epithelium (RPE) as well as the retina itself. This has been of benefit to date in human clinical trials using AAV, where the disease target is in the RPE. However, many mutations predisposing to retinal disease are located in the photoreceptor cells, present in the neural retina and not the RPE; in this case the sub-retinal injection route may cause an effective “loss” of therapeutic AAV to the RPE. The avβ5 integrin receptor is highly expressed on the apical surface of the RPE, and is essential to the daily phagocytosis of the outer segment tips of photoreceptor cells. The transduction efficiency of AAV was tested in the retinas of β5−/− mice lacking this receptor and showing defects in photoreceptor outer segment phagocytosis. Following sub-retinal injection of AAV2/5-eGFP, fluorescence was found to be stronger and more widespread in the neural retina of β5−/− mice compared to wild-types with greatly reduced fluorescence in the RPE. Increased levels of the phagocytic signalling protein MFG-E8, the ligand for the avβ5 integrin receptor, is found to have a moderate inhibitory effect on AAV transduction of the retina. However the opposite effect is found when only the integrin-binding domain of MFG-E8, the RGD (Arginine-Glycine-Aspartic acid) domain, was increased. In this case RGD enhanced AAV-mediated retinal transduction relative to RPE transduction. These results are presented for their relevance for the design of AAV-based retinal gene therapy strategies strategies targeting retinal/photoreceptor cells. Full article
(This article belongs to the Special Issue Gene Therapy)
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Review

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682 KiB  
Review
Current Challenges and Future Directions in Recombinant AAV-Mediated Gene Therapy of Duchenne Muscular Dystrophy
by Takashi Okada and Shin'ichi Takeda
Pharmaceuticals 2013, 6(7), 813-836; https://doi.org/10.3390/ph6070813 - 27 Jun 2013
Cited by 31 | Viewed by 10946
Abstract
Various characteristics of adeno-associated virus (AAV)-based vectors with long-term safe expression have made it an exciting transduction tool for clinical gene therapy of Duchenne muscular dystrophy (DMD). Although host immune reactions against the vector as well as transgene products were detected in some [...] Read more.
Various characteristics of adeno-associated virus (AAV)-based vectors with long-term safe expression have made it an exciting transduction tool for clinical gene therapy of Duchenne muscular dystrophy (DMD). Although host immune reactions against the vector as well as transgene products were detected in some instances of the clinical studies, there have been promising observations. Methods of producing AAV vectors for considerable in vivo experimentation and clinical investigations have been developed and a number of studies with AAV vector-mediated muscle transduction were attempted. Notably, an intravenous limb perfusion transduction technique enables extensive transgene expression in the skeletal muscles without noticeable adverse events. Furthermore, cardiac transduction by the rAAV9-microdystrophin would be promising to prevent development of cardiac dysfunction. Recent achievements in transduction technology suggest that long-term transgene expression with therapeutic benefits in DMD treatment would be achieved by the rAAV-mediated transduction strategy with an adequate regimen to regulate host immune response. Full article
(This article belongs to the Special Issue Gene Therapy)
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419 KiB  
Review
The Liver as a Target Organ for Gene Therapy: State of the Art, Challenges, and Future Perspectives
by Frank Jacobs, Stephanie C. Gordts, Ilayaraja Muthuramu and Bart De Geest
Pharmaceuticals 2012, 5(12), 1372-1392; https://doi.org/10.3390/ph5121372 - 10 Dec 2012
Cited by 32 | Viewed by 12142
Abstract
The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision [...] Read more.
The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision in the absence of side effects. Liver sinusoids are highly specialized capillaries with a particular endothelial lining: the endothelium contains open fenestrae, whereas a basal lamina is lacking. Fenestrae provide a direct access of gene transfer vectors to the space of Disse, in which numerous microvilli from parenchymal liver cells protrude. The small diameter of fenestrae in humans constitutes an anatomical barrier for most gene transfer vectors with the exception of adeno-associated viral (AAV) vectors. Recent studies have demonstrated the superiority of novel AAV serotypes for hepatocyte-directed gene transfer applications based on enhanced transduction, reduced prevalence of neutralizing antibodies, and diminished capsid immune responses. In a landmark clinical trial, hemophilia B was successfully treated with an AAV8 human factor IX expressing vector. Notwithstanding significant progress, clinical experience with these technologies remains very limited and many unanswered questions warrant further study. Therefore, the field should continue to progress as it has over the past decade, cautiously and diligently. Full article
(This article belongs to the Special Issue Gene Therapy)
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442 KiB  
Review
Gene Therapy for the Treatment of Parkinson’s Disease: The Nature of the Biologics Expands the Future Indications
by Massimo S. Fiandaca, Krystof S. Bankiewicz and Howard J. Federoff
Pharmaceuticals 2012, 5(6), 553-590; https://doi.org/10.3390/ph5060553 - 4 Jun 2012
Cited by 8 | Viewed by 10943
Abstract
The pharmaceutical industry’s development of therapeutic medications for the treatment of Parkinson’s disease (PD) endures, as a result of the continuing need for better agents, and the increased clinical demand due to the aging population. Each new drug offers advantages and disadvantages to [...] Read more.
The pharmaceutical industry’s development of therapeutic medications for the treatment of Parkinson’s disease (PD) endures, as a result of the continuing need for better agents, and the increased clinical demand due to the aging population. Each new drug offers advantages and disadvantages to patients when compared to other medical offerings or surgical options. Deep brain stimulation (DBS) has become a standard surgical remedy for the effective treatment of select patients with PD, for whom most drug regimens have failed or become refractory. Similar to DBS as a surgical option, gene therapy for the treatment of PD is evolving as a future option. In the four different PD gene therapy approaches that have reached clinical trials investigators have documented an excellent safety profile associated with the stereotactic delivery, viral vectors and doses utilized, and transgenes expressed. In this article, we review the clinically relevant gene therapy strategies for the treatment of PD, concentrating on the published preclinical and clinical results, and the likely mechanisms involved. Based on these presentations, we advance an analysis of how the nature of the gene therapy used may eventually expand the scope and utility for the management of PD. Full article
(This article belongs to the Special Issue Gene Therapy)
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518 KiB  
Review
Lipothioureas as Lipids for Gene Transfection: A Review
by Marie Breton, Jeanne Leblond, Isabelle Tranchant, Daniel Scherman, Michel Bessodes, Jean Herscovici and Nathalie Mignet
Pharmaceuticals 2011, 4(10), 1381-1399; https://doi.org/10.3390/ph4101381 - 24 Oct 2011
Cited by 9 | Viewed by 8114
Abstract
Non-viral gene therapy requires innovative strategies to achieve higher transfection efficacy. A few years ago, our group proposed bioinspired lipids whoseinteraction with DNA was not based on ionic interactions, but on hydrogen bonds. We thusdeveloped lipids bearing a thiourea head which allowed an [...] Read more.
Non-viral gene therapy requires innovative strategies to achieve higher transfection efficacy. A few years ago, our group proposed bioinspired lipids whoseinteraction with DNA was not based on ionic interactions, but on hydrogen bonds. We thusdeveloped lipids bearing a thiourea head which allowed an interaction with DNAphosphates through hydrogen bonds. After a proof of concept with a lipid bearing threethiourea functions, a molecular and cellular screening was performed by varying all partsof the lipids: the hydrophobic anchor, the spacer, the linker, and the thiourea head. Twolipothiourea-based structures were identified as highly efficient in vitro transfecting agents.The lipothioureas were shown to reduce non specific interactions with cell membranes anddeliver their DNA content intracellularly more efficiently, as compared to cationiclipoplexes. These lipids could deliver siRNA efficiently and allowed specific cell targetingin vitro. In vivo, thiourea lipoplexes presented a longer retention time in the blood and lessaccumulation in the lungs after an intravenous injection in mice. They also inducedluciferase gene expression in muscle and tumor after local administration in mice.Therefore, these novel lipoplexes represent an excellent alternative to cationic lipoplexes astransfecting agents. In this review we will focus on the structure activity studies thatpermitted the identification of the two most efficient thiourea lipids. Full article
(This article belongs to the Special Issue Gene Therapy)
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