Special Issue "Gene Therapy"

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A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (31 July 2011)

Special Issue Editors

Guest Editor
Prof. Dr. Yvonne Perrie (Website)

Chair in Drug Delivery, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
Interests: liposomes; gene therapy; vaccines; colloidal systems; pharmaceutics; pharmaceutical education; drug delivery
Guest Editor
Dr. Defang Ouyang

Aston Pharmacy School, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
Phone: +44 (0) 121 204 4021
Interests: design, physicochemical characterization and development of non-viral systems for gene delivery; stability of protein/peptide formulation using physicochemical methods and computer simulation

Keywords

  • gene therapy
  • gene delivery
  • siRNA
  • antisense therapy
  • viral vectors
  • non-viral vectors

Published Papers (6 papers)

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Research

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Open AccessArticle Hydrotalcite Intercalated siRNA: Computational Characterization of the Interlayer Environment
Pharmaceutics 2012, 4(2), 296-313; doi:10.3390/pharmaceutics4020296
Received: 17 March 2012 / Revised: 4 June 2012 / Accepted: 4 June 2012 / Published: 7 June 2012
Cited by 4 | PDF Full-text (860 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Using molecular dynamics (MD) simulations, we explore the structural and dynamical properties of siRNA within the intercalated environment of a Mg:Al 2:1 Layered Double Hydroxide (LDH) nanoparticle. An ab initio force field (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies: [...] Read more.
Using molecular dynamics (MD) simulations, we explore the structural and dynamical properties of siRNA within the intercalated environment of a Mg:Al 2:1 Layered Double Hydroxide (LDH) nanoparticle. An ab initio force field (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies: COMPASS) is used for the MD simulations of the hybrid organic-inorganic systems. The structure, arrangement, mobility, close contacts and hydrogen bonds associated with the intercalated RNA are examined and contrasted with those of the isolated RNA. Computed powder X-ray diffraction patterns are also compared with related LDH-DNA experiments. As a method of probing whether the intercalated environment approximates the crystalline or rather the aqueous state, we explore the stability of the principle parameters (e.g., the major groove width) that differentiate both A- and A'- crystalline forms of siRNA and contrast this with recent findings for the same siRNA simulated in water. We find the crystalline forms remain structurally distinct when intercalated, whereas this is not the case in water. Implications for the stability of hybrid LDH-RNA systems are discussed. Full article
(This article belongs to the Special Issue Gene Therapy)
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Open AccessArticle Exploring the Correlation Between Lipid Packaging in Lipoplexes and Their Transfection Efficacy
Pharmaceutics 2011, 3(4), 848-864; doi:10.3390/pharmaceutics3040848
Received: 15 September 2011 / Revised: 7 November 2011 / Accepted: 10 November 2011 / Published: 18 November 2011
Cited by 9 | PDF Full-text (1107 KB) | HTML Full-text | XML Full-text
Abstract
Whilst there is a large body of evidence looking at the design of cationic liposomes as transfection agents, correlates of formulation to function remain elusive. In this research, we investigate if lipid packaging can give further insights into transfection efficacy. DNA lipoplexes [...] Read more.
Whilst there is a large body of evidence looking at the design of cationic liposomes as transfection agents, correlates of formulation to function remain elusive. In this research, we investigate if lipid packaging can give further insights into transfection efficacy. DNA lipoplexes composed of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) in combination with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 1,2-stearoyl-3-trimethylammonium-propane (DSTAP) were prepared by the lipid hydration method. Each of the formulations was prepared by hydration in dH2O or phosphate buffer saline (PBS) to investigate the effect of buffer salts on lipoplex physicochemical characteristics and in vitro transfection. In addition, Langmuir monolayer studies were performed to investigate any possible correlation between lipid packaging and liposome attributes. Using PBS, rather than dH2O, to prepare the lipoplexes increased the size of vesicles in most of formulations and resulted in variation in transfection efficacies. However, one combination of lipids (DSPE:DOTAP) could not form liposomes in PBS, whilst the DSPE:DSTAP combination could not form liposomes in either aqueous media. Monolayer studies demonstrated saturated lipid combinations offered dramatically closer molecular packing compared to the other combinations which could suggest why this lipid combination could not form vesicles. Of the lipoplexes prepared, those formulated with DSTAP showed higher transfection efficacy, however, the effect of buffer on transfection efficiency was formulation dependent. Full article
(This article belongs to the Special Issue Gene Therapy)
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Open AccessArticle Fourth Generation Phosphorus-Containing Dendrimers: Prospective Drug and Gene Delivery Carrier
Pharmaceutics 2011, 3(3), 458-473; doi:10.3390/pharmaceutics3030458
Received: 30 June 2011 / Revised: 25 July 2011 / Accepted: 3 August 2011 / Published: 5 August 2011
Cited by 14 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
Research concerning new targeting delivery systems for pharmacologically active molecules and genetic material is of great importance. The aim of the present study was to investigate the potential of fourth generation (P4) cationic phosphorus-containing dendrimers to bind fluorescent probe 8-anilino-1-naphthalenesulfonate (ANS), anti-neoplastic [...] Read more.
Research concerning new targeting delivery systems for pharmacologically active molecules and genetic material is of great importance. The aim of the present study was to investigate the potential of fourth generation (P4) cationic phosphorus-containing dendrimers to bind fluorescent probe 8-anilino-1-naphthalenesulfonate (ANS), anti-neoplastic drug cisplatin, anti-HIV siRNA siP24 and its capability to deliver green fluorescent protein gene (pGFP) into cells. The interaction between P4 and ANS (as the model drug) was investigated. The binding constant and the number of binding centers per one molecule of P4 were determined. In addition, the dendriplex between P4 and anti-HIV siRNA siP24 was characterized using circular dichroism, fluorescence polarization and zeta-potential methods; the average hydrodynamic diameter of the dendriplex was calculated using zeta-size measurements. The efficiency of transfection of pGFP using P4 was determined in HEK293 cells and human mesenchymal stem cells, and the cytotoxicity of the P4-pGFP dendriplex was studied. Furthermore, enhancement of the toxic action of the anti-neoplastic drug cisplatin by P4 dendrimers was estimated. Based on the results, the fourth generation cationic phosphorus-containing dendrimers seem to be a good drug and gene delivery carrier candidate. Full article
(This article belongs to the Special Issue Gene Therapy)
Open AccessArticle Self-Assembled Lipoplexes of Short Interfering RNA (siRNA) Using Spermine-Based Fatty Acid Amide Guanidines: Effect on Gene Silencing Efficiency
Pharmaceutics 2011, 3(3), 406-424; doi:10.3390/pharmaceutics3030406
Received: 13 May 2011 / Revised: 20 June 2011 / Accepted: 5 July 2011 / Published: 13 July 2011
Cited by 6 | PDF Full-text (420 KB) | HTML Full-text | XML Full-text
Abstract
Four guanidine derivatives of N4,N9-diacylated spermine have been designed, synthesized, and characterized. These guanidine-containing cationic lipids bound siRNA and formed nanoparticles. Two cationic lipids with C18 unsaturated chains, N1,N12-diamidino-N4, [...] Read more.
Four guanidine derivatives of N4,N9-diacylated spermine have been designed, synthesized, and characterized. These guanidine-containing cationic lipids bound siRNA and formed nanoparticles. Two cationic lipids with C18 unsaturated chains, N1,N12-diamidino-N4,N9-dioleoylspermine and N1,N12-diamidino-N4-linoleoyl-N9-oleoylspermine, were more efficient in terms of GFP expression reduction compared to the other cationic lipids with shorter C12 (12:0) and very long C22 (22:1) chains. N1,N12-Diamidino-N4-linoleoyl-N9-oleoylspermine siRNA lipoplexes resulted in GFP reduction (26%) in the presence of serum, and cell viability (64%). These data are comparable to those obtained with TransIT TKO. Thus, cationic lipid guanidines based on N4,N9-diacylated spermines are good candidates for non-viral delivery of siRNA to HeLa cells using self-assembled lipoplexes. Full article
(This article belongs to the Special Issue Gene Therapy)
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Review

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Open AccessReview Polyamidoamine Dendrimer Conjugates with Cyclodextrins as Novel Carriers for DNA, shRNA and siRNA
Pharmaceutics 2012, 4(1), 130-148; doi:10.3390/pharmaceutics4010130
Received: 4 January 2012 / Revised: 20 January 2012 / Accepted: 20 January 2012 / Published: 1 February 2012
Cited by 13 | PDF Full-text (1131 KB) | HTML Full-text | XML Full-text
Abstract
Gene, short hairpin RNA (shRNA) and small interfering RNA (siRNA) delivery can be particularly used for the treatment of diseases by the entry of genetic materials mammalian cells either to express new proteins or to suppress the expression of proteins, respectively. Polyamidoamine [...] Read more.
Gene, short hairpin RNA (shRNA) and small interfering RNA (siRNA) delivery can be particularly used for the treatment of diseases by the entry of genetic materials mammalian cells either to express new proteins or to suppress the expression of proteins, respectively. Polyamidoamine (PAMAM) StarburstTM dendrimers are used as non-viral vectors (carriers) for gene, shRNA and siRNA delivery. Recently, multifunctional PAMAM dendrimers can be used for the wide range of biomedical applications including intracellular delivery of genes and nucleic acid drugs. In this context, this review paper provides the recent findings on PAMAM dendrimer conjugates with cyclodextrins (CyDs) for gene, shRNA and siRNA delivery. Full article
(This article belongs to the Special Issue Gene Therapy)
Open AccessReview Adenovirus Vector-Derived VA-RNA-Mediated Innate Immune Responses
Pharmaceutics 2011, 3(3), 338-353; doi:10.3390/pharmaceutics3030338
Received: 19 May 2011 / Revised: 27 June 2011 / Accepted: 5 July 2011 / Published: 11 July 2011
Cited by 7 | PDF Full-text (2839 KB) | HTML Full-text | XML Full-text
Abstract
The major limitation of the clinical use of replication-incompetent adenovirus (Ad) vectors is the interference by innate immune responses, including induction of inflammatory cytokines and interferons (IFN), following in vivo application of Ad vectors. Ad vector-induced production of inflammatory cytokines and IFNs [...] Read more.
The major limitation of the clinical use of replication-incompetent adenovirus (Ad) vectors is the interference by innate immune responses, including induction of inflammatory cytokines and interferons (IFN), following in vivo application of Ad vectors. Ad vector-induced production of inflammatory cytokines and IFNs also results in severe organ damage and efficient induction of acquired immune responses against Ad proteins and transgene products. Ad vector-induced innate immune responses are triggered by the recognition of Ad components by pattern recognition receptors (PRRs). In order to reduce the side effects by Ad vector-induced innate immune responses and to develop safer Ad vectors, it is crucial to clarify which PRRs and which Ad components are involved in Ad vector-induced innate immune responses. Our group previously demonstrated that myeloid differentiating factor 88 (MyD88) and toll-like receptor 9 (TLR9) play crucial roles in the Ad vector-induced inflammatory cytokine production in mouse bone marrow-derived dendritic cells. Furthermore, our group recently found that virus associated-RNAs (VA-RNAs), which are about 160 nucleotide-long non-coding small RNAs encoded in the Ad genome, are involved in IFN production through the IFN-β promoter stimulator-1 (IPS-1)-mediated signaling pathway following Ad vector transduction. The aim of this review is to highlight the Ad vector-induced innate immune responses following transduction, especially VA-RNA-mediated innate immune responses. Our findings on the mechanism of Ad vector-induced innate immune responses should make an important contribution to the development of safer Ad vectors, such as an Ad vector lacking expression of VA-RNAs. Full article
(This article belongs to the Special Issue Gene Therapy)

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