Li Chengwen
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 5R01AI080726-03 from National Institute Of Allergy And Infectious Diseases
Keywords: adeno-associated viral vector; Adverse effects; Alanine; Animal Model; Antigen Presentation; Antigens; Attenuated; base; Binding (Molecular Function); Bortezomib; Capsid; Capsid Proteins; Cell Line; Cell Nucleus; Cell surface; Cells; cellular transduction; Clinical; Clinical Trials; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dependovirus; Detection; Dose; Drug Formulations; Engineering; Ensure; Epitopes; Epstein-Barr Virus Nuclear Antigens; Failure (biologic function); Gene Expression; gene therapy; Gene Transduction Agent; Genetic Transcription; Glycine; Goals; Hemophilia B; Hepatocyte; Human; Human Herpesvirus 4; Immune; Immune response; Immune system; immunogenic; immunogenicity; Immunosuppressive Agents; improved; In Vitro; in vivo; inhibitor/antagonist; Injection of therapeutic agent; Killings; Kinetics; Liver; Mediating; Memory; MG132; MHC Class I Genes; Monitor; mouse model; Mus; Muscle; mutant; Natural immunosuppression; novel; novel strategies; OVA-8; Pathway interactions; Peptides; Pharmaceutical Preparations; pre-clinical; prevent; Proteasome Inhibitor; Proteins; Protocols documentation; public health relevance; recombinant virus; research study; response; Route; Safety; Serotyping; T-Lymphocyte; Testing; Therapeutic; therapeutic gene; Time; tool; trafficking; transgene expression; uptake; vector; vector genome; Viral Proteins; Virus
Relevance: Lay summary Adeno-associated virus (AAV) has been used in over 50 clinical trials and proves to be very promising for gene therapy, due to long-term therapeutic gene expression after delivery of AAV vectors. Recently, data from one clinical trial for hemophilia B suggested that AAV2 could induce an immune response and thus eliminate AAV2 infected liver cells. However, the results from a mouse model study did not support these findings. One explanation of these contradictory results could be the weak immunogenic activity of AAV capsids in mice. To more accurately mimic the clinical trial and establish an appropriate mouse model, we propose to insert a strong immunogen into AAV2 capsid and use these mutant AAV capsids to make recombinant virus. After injection of these viruses into mouse, we will investigate whether immunogen specific CTLs eliminate AAV2 transduced target cells in mice. Additionally, to reduce any immune response elicited by the AAV capsid, we will insert the Epstein-Barr virus product EBNA-1 into a non-essential region of the AAV capsid. We will test whether EBNA-1 will mediate inhibition of an immune response and prevent eradication of AAV infected cells. The long-term goals of this proposal are to critically evaluate the immune response to AAV-infected cells and to develop a novel AAV vector that will evade an immune response without compromising function, thus improving AAV as a gene therapy tool and enhancing its therapeutic value
Project start date: 2009-12-01
Project end date: 2014-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01AI080726-03 (2012): $326804
Sponsored Links Excellgen http://Excellgen.com
