Special Issue "Gene Therapy"

Guest Editor
Prof. Dr. Yvonne Perrie
Aston Pharmacy School, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK
Website: http://www1.aston.ac.uk/lhs/staff/az-index/perriey/
E-Mail: y.perrie@aston.ac.uk
Phone: +44 1212 043991
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
E-Mail: d.ouyang@aston.ac.uk
Phone: +44 (0) 121 204 4009
Interests: design, physicochemical characterization and development of non-viral systems for gene delivery; stability of protein/peptide formulation using physicochemical methods and computer simulation

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

Title: Phosphorus-containing Dendrimer of 4 Generation – Perspective Drug and Gene Delivery Carrier
Authors: Dzmitry Shcharbin ¹, Volha Dzmitruk ¹, Antos Shakhbazau ², Natalya Goncharova ³, Ihar Seviaryn ³, Svetlana Kosmacheva ³, Mihail Potapnev ³, Elzbieta Pedziwiatr-Werbicka ⁴, Maria Bryszewska ⁴ and Jean-Pierre Majoral ⁵
Affiliations: ¹ Institute of Biophysics and Cell Engineering of NASB, Minsk, Belarus
² Institute of Genetics and Cytology of NASB, Minsk, Belarus
³ Republic Center for Hematology and Transfusiology, Minsk, Belarus
⁴ University of Lodz, Lodz, Poland
⁵ Laboratorie de Chimie de Coordination, CNRS, Toulouse, France
Abstract: The research on new targeting delivery systems of pharmacologically active molecules and genetic material is of great importance. The aim of the work is to investigate the potential of cationic phosphorus-containing dendrimer of 4 generation (P4) as drug and gene delivery carrier. We studied the interaction between P4 and model drug – fluorescent probe ANS. The binding constant and the number of binding centers per one molecule of P4 was determined. At the second step the dendriplex between P4 and anti-HIV siRNA siP24 was characterized by means of circular dichroism, fluorescence polarization, zeta-potential methods; an average hydrodynamic diameter of dendriplex was evaluated by zeta-size measurements. The third part of our work includes estimation of the efficiency of transfection of green fluorescent protein gene (pGFP) by P4 in HEK293 cells and mesenchymal stem cells; the cytotoxicity of P4-pGFP dendriplex was also checked. As the conclusion it can be stated that cationic phosphorus-containing dendrimer (P4) of 4 generation is good candidate to be applied as drug and gene delivery carrier.
Keywords: phosphorus-containing dendrimer; drug delivery; gene delivery; dendriplex characterization; transfection; mesenchymal stem cells

Title: The Adenovirus-Mediated Immune Response and VA-RNA
Author: Hiroyuki Mizuguchi
Affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences,  Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Abstract: The major limitation of clinical use of replication-incompetent adenovirus (Ad) vectors is innate immune responses, including induction of inflammatory cytokines and interferons, following in vivo application of Ad vectors.  Ad vector-induced production of inflammatory cytokines and interferons also results in severe organs damages and efficient induction of acquired immune responses against Ad proteins and transgene products.  Ad vector-induced innate immune responses are triggered by recognizing the Ad components by pattern recognition receptors (PRRs).  In order to reduce the side effects by Ad vector-induced innate immune responses and to develop the safer Ad vectors, it is highly crucial to clarify which PRRs and which of the 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) plays a crucial role on 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 RNA encoded in the Ad genome at bp 10620-10779 and bp 10876-11038, are involved in interferon production through 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-RNAs-mediated innate immune responses.  The findings in the mechanism of the Ad vector-induced innate immune responses would largely contribute to the development of the safer Ad vectors, such as an Ad vector lacking expression of VA-RNAs.
Key words: adenovirus vector; VA-RNA; gene therapy; innate immunity

Type of Paper: Article
Title: Polyamidoamine Dendrimer Conjugates with Cyclodextrins as Novel Carriers for DNA and siRNA
Author: Hidetoshi Arima
Affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan; E-Mail: arimah@gpo.kumamoto-u.ac.jp
Abstract: Gene and siRNA delivery can particularly be used for the treatment of diseases by the insertion of genetic materials into mammalian cells either to express new proteins or to prevent the expression of proteins, respectively.  Polyamidoamine (PAMAM) dendrimers, of which ease of synthesis with controlled structure and size, minimal cytotoxicity, and high transfection efficiencies, are used as a support material for gene and siRNA delivery. Recently, multifunctional PAMAM dendrimers can be used for the wide range of biomedical applications including the interaction and intracellular delivery of genetic materials. In this context, this review paper provides the recent development on PAMAM dendrimer conjugates with cyclodextrins (CyDs) having multifunctional moieties for gene and siRNA delivery.
Keywords: cyclodextrin, dendrimer, conjugate, DNA delivery, multifunction