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Nonviral Gene Therapy—The Challenge of Mobilizing DNA

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Somatic Genome Manipulation

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Abstract

Genetic treatment of human disease is based on the feasibility of transferring exogenous genes, engineered in the laboratory for optimized and persistent expression, to relevant cells or tissues in the patient. Viruses are natural carriers of genetic information, and have been successfully adapted as gene vehicles (‘vectors’) in several recent clinical trials. Therapeutic administration of gene-encoding plasmid DNA—either ‘naked’ or wrapped in cationic complexes—represents an alternative approach that is traditionally considered safer, less immunogenic, and more cost-effective than virus-derived vectors. However, plasmid DNA is confronted by numerous in vivo barriers, and nonviral gene delivery methods have generally suffered from low gene delivery efficacy and short-term gene expression. Hence, to reach the prominent goal of mobilizing therapeutic DNA and facilitating uptake of DNA in the nuclei of desired cells, additional action is required. Such actions may serve to increase cell permeability, for example by exposing target cells to high pressure or an externally applied electrical field. Other strategies aim at mimicking viral gene transfer by engineering synthetic particles of lipids or polymers complexed with plasmid DNA. This chapter reviews the current status of nonviral gene transfer with primary focus on the DNA and its mobilization. The major barriers to nonviral gene delivery are discussed and the potential of minicircle DNA, devoid of bacterial DNA, and the adaptation of DNA transposable elements for genomic gene insertion are described. A short glimpse into current nonviral gene therapy trials, with particular focus on current attempts to treat cystic fibrosis, is also provided.

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Acknowledgments

Studies of nonviral vector technogies in the laboratory of JGM have been carried out through support from the Lundbeck Foundation, the Novo Nordisk Foundation, Aase og Ejnar Danielsens Fond, Agnes og Poul Friis Fond, Kgl. Hofbuntmager Aage Bangs Fond, Grosserer A. V. Lykfeldt og Hustrus Legat, Else og Mogens Wedell-Wedellsborgs Fond, Fonden af 17-12-1981, Kong Christian den Tiendes Fond, Civilingeniør Frode V. Nyegaard og hustrus Fond, Clara Hansens Mindelegat, Kirsten Anthonius Mindelegat, Snedkermester Sophus Jacobsen and Hustru Astrid Jacobsens Fond og Frits, Georg og Marie Cecilie Gluds Legat. JGM is the director of Gene Therapy Initiative Aarhus (GTI-Aarhus) funded by the Lundbeck Foundation and a member of the Aarhus Research Center for Innate Immunology (ARCII) established through funding by the AU-Ideas program at Aarhus University.

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  1. Department of Biomedicine ,Faculty of Health, Aarhus University, Wilh. Meyers Allé 4, 8000, Aarhus C, Denmark

    Prof. Jacob Giehm Mikkelsen MD

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  1. Prof. Jacob Giehm Mikkelsen MD
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Correspondence to Jacob Giehm Mikkelsen MD .

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  1. Potato Research Centre, Agriculture and Agri-Food Canada, Government of Canada, Fredericton, New Brunswick, Canada

    Xiu-Qing Li

  2. Plant Science Department, McGill University, Sainte-Anne-de-Bellevue, Québec, Canada

    Danielle J. Donnelly

  3. Department of Biomedicine, Aarhus University, Herning, Denmark

    Thomas G. Jensen

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Mikkelsen, J. (2015). Nonviral Gene Therapy—The Challenge of Mobilizing DNA. In: Li, XQ., Donnelly, D., Jensen, T. (eds) Somatic Genome Manipulation. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2389-2_4

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