Current Gene Therapy (v.11, #3)

Editorial by Ignacio Anegon (154-154).
Current Gene Therapy was born with the XXI century, as a reviews journal for gene therapy, a relatively new field ofbiomedical sciences that was gaining in maturity and solidity. Gene therapy was the result of a progressive merging of severalscientific disciplines; genetics, molecular biology, virology, immunology and the clinical research of various organs and tissuesaffected by genetic diseases. Gene therapy has progressively evolved to include areas of diseases that are not directly of geneticorigin, such as cancer or infectious diseases. Gene therapy is now a diverse and dynamic domain embracing almost everydisease and pathophysiological process.During its first 10 years, Current Gene Therapy reflected the evolution of gene therapy and also aimed at pointing towardsnew directions and objectives of the field that appeared as promising.During this time, Current Gene Therapy has increased its visibility and impact. This was largely due to the strength of genetherapy’s achievements that despite drawbacks and obstacles has generated very significant basic scientific knowledge andsome clinical successes. Future applications of gene therapy as well as translational and basic research in the field of genetherapy will likely continue to increase and Current Gene Therapy will be an attentive partner for all basic and clinicalresearchers in the field. The second major asset of the journal has been the very high scientific level of authors submittingmanuscripts and of reviewers. Sincere acknowledgments to them all and an enthusiastic invitation for more years of work,together on Current Gene Therapy.

Gene Therapy and Targeted Toxins for Glioma by Maria G. Castro, Marianela Candolfi, Kurt M. Kroeger, Gwendalyn D. King, James F. Curtin, Kader Yagiz, Yohei Mineharu, Hikmat Assi, Mia Wibowo, A.K.M. Ghulam Muhammad, David Foulad, Mariana Puntel, Pedro R. Lowenstein (155-180).
The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressivewith a mean survival time of 15-18 months from diagnosis to death. Current treatment modalities are unable to significantlyprolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developingnovel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for gliomaincluding xenograft, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued inpreclinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins,oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigmsaim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence.While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitionedinto clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic,targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robustas preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed,and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide apowerful approach to treat and manage brain tumors.

Adeno-Associated Virus (AAV) Vectors in the CNS by Thomas J. McCown (181-188).
Adeno-associated virus (AAV) vectors exhibit a number of properties that have made this vector system an excellentchoice for both CNS gene therapy and basic neurobiological investigations. In vivo, the preponderance of AAVvector transduction occurs in neurons where it is possible to obtain long-term, stable gene expression with very little accompanyingtoxicity. Promoter selection, however, significantly influences the pattern and longevity of neuronal transductiondistinct from the tropism inherent to AAV vectors. AAV vectors have successfully manipulated CNS function using awide variety of approaches including expression of foreign genes, expression of endogenous genes, expression of antisenseRNA and expression of RNAi. With the discovery and characterization of different AAV serotypes, as well as thecreation of novel chimeric serotypes, the potential patterns of in vivo vector transduction have been expanded substantially,offering alternatives to the more studied AAV 2 serotype. Furthermore, the development of specific AAV chimerasoffers the potential to further refine targeting strategies. These different AAV serotypes also provide a solution to the immunesilencing that proves to be a realistic likelihood given broad exposure of the human population to the AAV 2 serotype.These advantageous CNS properties of AAV vectors have fostered a wide range of clinically relevant applicationsincluding Parkinson’s disease, lysosomal storage diseases, Canavan’s disease, epilepsy, Huntington’s disease and ALS. Inmany cases the proposed therapies have progressed to phase I/II clinical trials. Each individual application, however, presentsa unique set of challenges that must be solved in order to attain clinically effective gene therapies.

MVA and NYVAC as Vaccines against Emergent Infectious Diseases and Cancer by Carmen E. Gomez, Jose L. Najera, Magdalena Krupa, Beatriz Perdiguero, Mariano Esteban (189-217).
Recombinants based on poxviruses have been used extensively as gene delivery systems to study many biologicalfunctions of foreign genes and as vaccines against many pathogens, particularly in the veterinary field. Based onsafety record, efficient expression and ability to trigger specific immune responses, two of the most promising poxvirusvectors for human use are the attenuated modified vaccinia virus Ankara (MVA) and the Copenhagen derived NYVACstrains. Because of the scientific and clinical interest in these two vectors, here we review their biological characteristics,with emphasis on virus-host cell interactions, viral immunomodulators, gene expression profiling, virus distribution inanimals, and application as vaccines against different pathogens and tumors.

Current Advances in Retroviral Gene Therapy by Youngsuk Yi, Moon Jong Noh, Kwan Hee Lee (218-228).
There have been major changes since the incidents of leukemia development in X-SCID patients after thetreatments using retroviral gene therapy. Due to the risk of oncogenesis caused by retroviral insertional activation of hostgenes, most of the efforts focused on the lentiviral therapies. However, a relative clonal dominance was detected in a patientwith β-thalassemia Major, two years after the subject received genetically modified hematopoietic stem cells usinglentiviral vectors. This disappointing result of the recent clinical trial using lentiviral vector tells us that the current andmost advanced vector systems does not have enough safety. In this review, various safety features that have been tried forthe retroviral gene therapy are introduced and the possible new ways of improvements are discussed. Additional feature ofchromatin insulators, co-transduction of a suicidal gene under the control of an inducible promoter, conditional expressionof the transgene only in appropriate target cells, targeted transduction, cell type-specific expression, targeted local administration,splitting of the viral genome, and site specific insertion of retroviral vector are discussed here.

BMP-9 Induced Osteogenic Differentiation of Mesenchymal Stem Cells: Molecular Mechanism and Therapeutic Potential by Gaurav Luther, Eric R. Wagner, Gaohui Zhu, Quan Kang, Qing Luo, Joseph Lamplot, Yang Bi, Xiaoji Luo, Jinyong Luo, Chad Teven, Qiong Shi, Stephanie H. Kim, Jian-Li Gao, Enyi Huang, Ke Yang, Richard Rames, Xing Liu, Mi Li, Ning Hu, Hong Liu, Yuxi Su, Liang Chen, Bai-Cheng He, Guo-Wei Zuo, Zhong-Liang Deng, Russell R. Reid, Hue H. Luu, Rex C. Haydon, Tong-Chuan He (229-240).
Promoting osteogenic differentiation and efficacious bone regeneration have the potential to revolutionize thetreatment of orthopaedic and musculoskeletal disorders. Mesenchymal Stem Cells (MSCs) are bone marrow progenitorcells that have the capacity to differentiate along osteogenic, chondrogenic, myogenic, and adipogenic lineages. Differentiationalong these lineages is a tightly controlled process that is in part regulated by the Bone Morphogenetic Proteins(BMPs). BMPs 2 and 7 have been approved for clinical use because their osteoinductive properties act as an adjunctivetreatment to surgeries where bone healing is compromised. BMP-9 is one of the least studied BMPs, and recent in vitroand in vivo studies have identified BMP-9 as a potent inducer of osteogenic differentiation in MSCs. BMP-9 exhibits significantmolecular cross-talk with the Wnt/ β-catenin and other signaling pathways, and adenoviral expression of BMP-9in MSCs increases the expression of osteogenic markers and induces trabecular bone and osteiod matrix formation. Furthermore,BMP-9 has been shown to act synergistically in bone formation with other signaling pathways, including Wnt/β-catenin, IGF, and retinoid signaling pathways. These results suggest that BMP-9 should be explored as an effectivebone regeneration agent, especially in combination with adjuvant therapies, for clinical applications such as large segmentalbony defects, non-union fractures, and/or spinal fusions.