Nature Medicine
- 12, 348 - 353 (2006)
Published online: 19 February 2006; | doi:10.1038/nm1365
Effective gene therapy with nonintegrating lentiviral vectorsRafael J Yáñez-Muñoz1, 2, 10, 11, Kamaljit S Balaggan3, 11, Angus MacNeil3, Steven J Howe1, Manfred Schmidt4, 5, Alexander J Smith3, Prateek Buch3, Robert E MacLaren3, Patrick N Anderson6, Susie E Barker3, Yanai Duran3, Cynthia Bartholomae4, 5, Christof von Kalle4, 5, 7, John R Heckenlively8, Christine Kinnon1, Robin R Ali1, 3 & Adrian J Thrasher1, 91
Molecular Immunology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. 2
Centre for Medical Oncology, Institute of Cancer and the CR-UK Clinical Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK. 3
Division of Molecular Therapy, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK. 4
Department of Internal Medicine I, University Hospital, Hugstetter Strasse 55, 79106 Freiburg and Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, 79104 Freiburg, Germany. 5
National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. 6
Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. 7
Cincinnati Children's Research Foundation, Molecular and Gene Therapy Program, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA. 8
Kellogg Eye Center, 1000 Wall Street, Room 541, Ann Arbor, Michigan 48105, USA. 9
Department of Immunology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK. 10
Present address: Nuclear Biology Group, Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Tower, Guy's Hospital, London SE1 9RT, UK. 11
These authors contributed equally to this work.
Correspondence should be addressed to Rafael J Yáñez-Muñoz rafael.yanez@genetics.kcl.ac.uk or Robin R Ali r.ali@ucl.ac.uk Retroviral and lentiviral vector integration into host-cell chromosomes carries with it a finite chance of causing insertional mutagenesis1. This risk has been highlighted by the induction of malignancy in mouse models, and development of lymphoproliferative disease in three individuals with severe combined immunodeficiency–X1 (refs. 2,3). Therefore, a key challenge for clinical therapies based on retroviral vectors is to achieve stable transgene expression while minimizing insertional mutagenesis. Recent in vitro studies have shown that integration-deficient lentiviral vectors can mediate stable transduction4,
5,
6. With similar vectors, we now show efficient and sustained transgene expression in vivo in rodent ocular and brain tissues. We also show substantial rescue of clinically relevant rodent models of retinal degeneration. Therefore, the high efficiency of gene transfer and expression mediated by lentiviruses can be harnessed in vivo without a requirement for vector integration. For therapeutic application to postmitotic tissues, this system substantially reduces the risk of insertional mutagenesis.
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