Current Gene Therapy (v.13, #5)

Manganese Superoxide Dismutase Gene Therapy Protects Against Irradiation- Induced Intestinal Injury by Chao Yang, Hai-Xu Chen, Yong Zhou, Min-Xia Liu, Yan Wang, Jie-Xi Wang, Su-Ping Ren, Ying Han, Ben-Yan Wu (305-314).
Radiation-induced intestinal injury is a common complication in radiotherapy for solid organ malignancies inabdomen or pelvis. However, currently there are no approved medical countermeasures for radiation-induced intestinal injury.Therefore, it is urgent to develop new treatments for radiation-induced intestinal injury. In the present study, wedemonstrated that bone marrow derived mesenchymal stem cells (MSCs) and overexpression of human manganese superoxidedismutase (MnSOD) could ameliorate radiation-induced intestinal syndrome. NOD/SCID mice received abdominalirradiation at a selected dose of 5 Gy, and then infused intravenously with MnSOD-MSCs. Mice body weight, survivaland diarrhea were monitored for 30-days. Colonization and differentiation of MnSOD-MSCs in the irradiated intestinewere analyzed by histological and immunohistochemical methods. Consequently, our data demonstrated that intravenousadministration of MnSOD-MSCs improved survival, decreased diarrhea occurrence and protected the small intestinalstructural integrity of irradiated mice. Moreover, intravenously transplanted MnSOD-MSCs could colonize the irradiatedintestine and repair injured sites. These findings suggested that MnSOD-MSCs may be an attractive and potential optionfor radiation-induced intestinal injury.

Dysfunction of peripheral nerves due to metabolic, toxic, infectious, or genetic causes is a common and debilitatingsyndrome resulting in sensory loss. Peripheral neuropathies are one of the most widespread neurological disorders,affecting nearly 20 million people in the United States alone. Pharmacologic treatment for peripheral neuropathies is oneof the most challenging fields in the clinical research. Sensory neurons are widely distributed and relatively inaccessible todirect drug delivery. Targeted delivery of neurotrophic factors to the primary sensory afferent for treatment of polyneuropathyby gene transfer approach offers the possibility of a highly selective targeted release of bioactive molecules withinthe nervous system. Preclinical studies with non-replicating herpes simplex virus (HSV)-based vectors injected into theskin to transduce neurons in the dorsal root ganglion (DRG) have demonstrated efficacy in preventing progression of sensoryneuropathy without any possible systemic side effects.

Targeted Multimodal Liposomes for Nano-delivery and Imaging: An Avenger for Drug Resistance and Cancer by Sneha Gurudevan, Rupinder K. Kanwar, Rakesh N. Veedu, Sreenivasan Sasidharan, Richard L. Kennedy, Ken Walder, Neerati Prasad, Jagat R. Kanwar (322-334).
Understanding the cellular target structure and thereby proposing the best delivery system to achieve sustainedrelease of drugs has always been a significant area of focus in biomedical research for translational benefits. Specific targetingof the receptors expressed on the target cell represents an effective strategy for increasing the pharmacological efficacyof the administered drug. Liposomes offer enhanced conveyance as a potential carrier of biomacromolecules such asanti-cancer proteins, drugs and siRNA for targeting tumour cell death. Commonly used liposomal constructs for varioustherapies are Doxil, Myocet, DepoCyt and Abraxanes. However, recent strategy of using multifunctional liposomes forthe sustained release of drugs with increased plasma residence time and monoclonal antibody-based targeting of tumourscoupled with imaging modalities have attracted enormous scientific attention. The ability of liposomes coated with specificligands such as Apo-E derived RGD R9 and Tat peptide, to reverse the conceptualisation of drug resistance and crossthe blood brain barrier, provides promising future for their use as an efficient drug delivery system. By outlining the recentadvancements and innovations in the established concept of liposomal drug delivery, this review will focus on themultifunctional liposomes as an emerging novel lipid based drug delivery system.

Advances in Recombinant Adeno-Associated Viral Vectors for Gene Delivery by Hilda Petrs-Silva, Rafael Linden (335-345).
Recombinant adeno-associated viral vectors (rAAV) have now been used in several clinical trials to treat a varietyof diseases, and are currently the preferred choice of many investigators in the field, due to both their low pathogenicityand immunogenicity compared with other viral vectors, as well as localized long-term gene expression, despitetheir limitations of DNA size packaging and speed of expression. Recently, a number of advances have led to new generationsof rAAV vectors, with improved features. This review addresses the various strategies employed to such effect,namely exploring distinct serotype tropisms, the production of mosaic and chimeric capsids, the selection of vectorsthrough directed evolution, the development of self-complementary vectors, the use of pharmacological adjuvants and theinduction of specific capsid mutations. Such approaches are expected to help the establishment of rAAV-based clinicalgene therapy in the near future.

Antibody-directed Double Suicide Gene Therapy Targeting of MUC1- Positive Leukemia Cells In Vitro and In Vivo by Xiao-Ya Dong, Wen-Qian Wang, Yu Zhao, Xu-Dong Li, Zhi-Gang Fang, Dong-Jun Lin, Ruo-Zhi Xiao, Ren-Wei Huang, Guang-Jin Pan, Jia-Jun Liu (346-357).
Our aim was to specifically transfer the cytosine deaminase (CD) and thymidine kinase (TK) genes into mucin1 (MUC1)-positive leukemia cells by anti-MUC1 antibody directed infection of replication-defective lentivirus and toevaluate the targeted cytotoxicity of double suicide genes to leukemia. The target gene vector (containing CD and TK)and envelope (containing GFP and anti-MUC1) and packaging plasmids were cotransfected into 293T cells to produce therecombinant lentivirus. Suicide genes in virus-infected leukemia cells (U937, Jurkat, and K562) were detected by westernblot. The cytotoxicity and bystander effect in vitro and the therapeutic effect in vivo were detected after treatment with theprodrugs. The results revealed that combined treatment with prodrug 5-fluorocytosine (5-FC) and ganciclovir (GCV) inhibitedleukemia cell growth and caused significant bystander effect than treatment with either prodrug alone. TK/GCVtreatment alone induced degeneration and cell death while the effect of CD/5-FC alone mainly caused vacuolar degenerationand necrosis. The addictive effects of combinatorial use of GCV and 5-FC mainly induced swelling of the mitochondriafollowed by necrosis of the leukemia cells. In vivo experiments revealed that both single and combinatorial prodrugtreatments could prolong the survival time of leukemic mice. In summary, anti-MUC1 antibody directed lentiviral vectorsuccessfully transduced dual suicide genes and exerted targeted cytotoxicity against MUC1 positive leukemia cells. Thistargeted lentiviral dual suicide gene delivering system provides a promising approach for clinical treatment of leukemia infuture.

Polymeric Systems as Nanodevices for siRNA Delivery by Marcio J. Tiera, Qin Shi, Hellen Franciane Gonçalves Barbosa, Julio C. Fernandes (358-369).
The delivery of small interfering RNAs (siRNAs) is a promising approach to silencing gene expression aimedat treating infections, cancer, neurodegenerative diseases and various other disorders. Recent progress in this area hasbeen achieved with nanodevices possessing multiple properties and assembled with new, biodegradable, synthetic polymersand polysaccharides. Different synthetic routes and multiple strategies, such as multilayer systems and stimuliresponsivepolymers, have been developed to attain high efficiencies. This review covers the most important, promisingand successful approaches to improve siRNA delivery. It is a concise report on multiple strategies employed, includingcell-specific delivery coupling ligands or antibodies with nanodevices to improve siRNA efficiency and specificity.

Helper Dependent Adenovirus Vectors: Progress and Future Prospects by Dan Cots, Assumpció Bosch, Miguel Chillón (370-381).
Sixteen years after Graham and coworkers described the most used system for generating helper-dependentadenovirus (HDAd) vectors, production systems have evolved considerably, and most resulting preparations have titres of1 1013 IU/ml (infection units/ml) and very low helper contamination levels (<0.1%). These advances in production, aswell as the attractive characteristics of these vectors (large insert capacity and low cell immune response compared withfirst-generation Ad vectors) make them very interesting for many research purposes as they have become more accessibleto the scientific community. In this review we summarise the latest strategies for producing HDAd vectors, describe themain areas of interest for which HDAd vectors are being used, and comment on the future prospects for HDAd vectors ingene therapy.