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Multifunctional nanocomplexes for gene transfer and gene therapy

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Abstract

DNA formulated into aggregates with polycationic reagents are referred to by a variety of terms including non-viral vectors, synthetic vectors, lipoplexes, polyplexes and more recently nanoparticles. The capacity for delivery of multiple genes, genomic-sized constructs and siRNA delivery, with a diversity of possible formulations, as well as the possibilities of improved efficiency of in vivo gene deliveries, means that nanoparticles, or nanocomplexes to reflect self-assembling systems, will be investigated with increasing vigour in the coming years. This review briefly outlines the applications and challenges for nanoparticle technologies in the field of gene therapy then focuses on the development of a specific kind of formulation, receptor-targeted nanocomplex (RTN), that we have found to be particularly useful in our gene therapy research. An overriding guiding concept that has emerged in the development of synthetic nanodelivery systems is the idea to develop formulations and structures that mimic viruses, whilst retaining the safety elements of synthetic, non-viral systems. RTNs have been optimised and developed for airway epithelial transfection, leading towards gene therapy for cystic fibrosis and for vascular transfection in vein grafts used in bypass surgery. The modular design of the RTN platform further allows for the testing of specific hypotheses relating to the structure and functional role of components in the formation of stable particles and in the transfection pathway, leading to their ultimate disassembly in the nucleus.

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Abbreviations

RTN:

Receptor-targeted nanocomplex

siRNA:

Short interfering RNA

RNAi:

RNA interference

SCID X1:

Severe combined immunodeficiency disease type X1

bp:

Base pairs

kb:

Kilobase pairs

nt:

Nucleotides

DOTMA:

1,2-Di-((Z)-octadec-9-enyloxy)-N,N,N-trimethylammonium propane chloride

DOPE:

Dioleoyl phosphatidylethanolamine

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Acknowledgements

I would like to thank my colleagues and collaborators over the years who contributed to the work on RTNs. In particular, Charles Coutelle and Bob Williamson from the former St. Mary’s Hospital Medical School, London (now Imperial College), Helen Hailes and Alethea Tabor from UCL Department of Chemistry, Jean McEwan from UCL Centre for Cardiovascular Biology and Medicine, Robin McAnulty from UCL Centre for Respiratory Research and Dr. Adam Jaffe from Great Ormond Street Hospital and UCL Institute of Child Health. Also, my Ph.D. students who have contributed to the work including Susie Barker, Elena Siapati, Shahla Salehi, Albert Kwok, Angelika Kritz and Gisli Jenkins and postdocs at ICH including Qing Hai Meng, Aris Tagalakis, Maria Manunta, Michele Writer, Aima Uduehi, Carolina Mailhos and Richard Parkes and Richard Harbottle from Imperial College. Thanks to the grant-funding bodies for supporting this work: Wellcome Trust, BBSRC, EPSRC, Cystic Fibrosis Trust, Sparks and North Bristol NHS Trust. My thanks also go to staff at Genex Biosystems Ltd. for their work on the translational development of RTN formulations.

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  1. Wolfson Centre for Gene Therapy of Childhood Disease, UCL Institute of Child Health, London, UK

    Stephen L. Hart

  2. Genex Biosystems Ltd., London, UK

    Stephen L. Hart

  3. Molecular Immunology Unit, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    Stephen L. Hart

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Hart, S.L. Multifunctional nanocomplexes for gene transfer and gene therapy. Cell Biol Toxicol 26, 69–81 (2010). https://doi.org/10.1007/s10565-009-9141-y

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