Affiliation: | 1. John Van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, U.K.;2. John Van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, U.K. MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, U.K. NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, U.K.;3. John Van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, U.K. Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, U.K. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia |
Abstract: | Viral vectors can be utilised to deliver therapeutic genes to diseased cells. Adeno-associated virus (AAV) is a commonly used viral vector that is favoured for its ability to infect a wide range of tissues whilst displaying limited toxicity and immunogenicity. Most humans harbour anti-AAV neutralising antibodies (NAbs) due to subclinical infections by wild-type virus during infancy and these pre-existing NAbs can limit the efficiency of gene transfer depending on the target cell type, route of administration and choice of serotype. Vector administration can also result in de novo NAb synthesis that could limit the opportunity for repeated gene transfer to diseased sites. A number of strategies have been described in preclinical models that could circumvent NAb responses in humans, however, the successful translation of these innovations into the clinical arena has been limited. Here, we provide a comprehensive review of the humoral immune response to AAV gene therapy in the ocular compartment. We cover basic AAV biology and clinical application, the role of pre-existing and induced NAbs, and possible approaches to overcoming antibody responses. We conclude with a framework for a comprehensive strategy for circumventing humoral immune responses to AAV in the future. |