A recent study proved the concept that rAAV-mediated intramuscular delivery of scFv immunoadhesins to rhesus macaques can generate sustained high serum levels of these inhibitors, and protect study animals from a high-dose SIV challenge. However, some of the treated animals in that study developed anti-immunoadhesin antibody responses, resulting in clearance of antiviral inhibitors. Immune clearance of this sort has been well documented in the rAAV gene-therapy literature: expression of foreign proteins from rAAVs in large animal models can in general elicit strong trangene-directed immunity, leading to host clearance of the expressed transgene. Indeed immune clearence remains a key challenge to further translational development of rAAV-delivered therapies. It is therefore necessary to better define immune processes contributing to anti-inhibitor antibody responses, and to develop novel strategies to prevent clearance of expressed transgenes. These are the main objectives of Project 2. We proposed the following studies to accomplish these objectives: 1). To limit transduction and antigen presentation of rAAV-immunoadhesin in unintended target cells and tissues by evaluating a panel of muscle specific promoters for promoter strength, tissue specificity and feasibility for use in the packaging size-limited rAAV genome. 2). To detarget rAAV transduction from antigen presenting cells by harnessing endogenous miRNAs for dendritic cell specific post-transcriptional transgene silencing. 3). To induce sustained systemic tolerance to immunoadhesin expression by hepatotropic rAAV8-mediated and liver-specific transduction. These studies will generate an AAV vector genome optimized to limit clearence of expressed transgenes, an objective critical to the therapeutic use of AAV vectors in many contexts.
rAAV-mediated delivery of anti-viral therapeutics is a promising approach to prevent and/or treat HIV infections. However, rAAV expression of anti-viral inhibitors in immune competent primates can occasionally elicit antibodies that interfere with the anti-viral activity of these inhibitors. This project will evaluate novel strategies for minimizing these anti-inhibitor antibody responses. In doing so, it will help improve the efficacy of AAV-delivered therapeutics useful for treating or preventing HIV-1 infection.
|Wang, Dan; Zhong, Li; Nahid, M Abu et al. (2014) The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin Drug Deliv 11:345-64|
|Wang, Dan; Gao, Guangping (2014) State-of-the-art human gene therapy: part I. Gene delivery technologies. Discov Med 18:67-77|
|Quinlan, Brian D; Joshi, Vinita R; Gardner, Matthew R et al. (2014) A double-mimetic peptide efficiently neutralizes HIV-1 by bridging the CD4- and coreceptor-binding sites of gp120. J Virol 88:3353-8|
|Wang, Dan; Gao, Guangping (2014) State-of-the-art human gene therapy: part II. Gene therapy strategies and clinical applications. Discov Med 18:151-61|
|Gao, Kai; Li, Mengxin; Zhong, Li et al. (2014) Empty Virions In AAV8 Vector Preparations Reduce Transduction Efficiency And May Cause Total Viral Particle Dose-Limiting Side-Effects. Mol Ther Methods Clin Dev 1:20139|
|Quinlan, Brian D; Gardner, Matthew R; Joshi, Vinita R et al. (2013) Direct expression and validation of phage-selected peptide variants in mammalian cells. J Biol Chem 288:18803-10|
|Stoica, Lorelei; Ahmed, Seemin S; Gao, Guangping et al. (2013) Gene transfer to the CNS using recombinant adeno-associated virus. Curr Protoc Microbiol Chapter 14:Unit14D.5|
|Gruntman, Alisha M; Bish, Lawrence T; Mueller, Christian et al. (2013) Gene transfer in skeletal and cardiac muscle using recombinant adeno-associated virus. Curr Protoc Microbiol Chapter 14:Unit 14D.3|
|Venkatesh, Aditya; Ma, Shan; Langellotto, Fernanda et al. (2013) Retinal gene delivery by rAAV and DNA electroporation. Curr Protoc Microbiol Chapter 14:Unit 14D.4|
|Ahmed, Seemin Seher; Li, Jia; Godwin, Jonathan et al. (2013) Gene transfer in the liver using recombinant adeno-associated virus. Curr Protoc Microbiol Chapter 14:Unit14D.6|