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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI100263-01
Application #
8311212
Study Section
Special Emphasis Panel (ZAI1-RB-A (J1))
Project Start
2012-04-01
Project End
2012-11-30
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$539,039
Indirect Cost
$136,455
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Martinez-Navio, José M; Fuchs, Sebastian P; Pedreño-López, Sònia et al. (2016) Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys. Mol Ther 24:76-86
Gardner, Matthew R; Fellinger, Christoph H; Prasad, Neha R et al. (2016) CD4-Induced Antibodies Promote Association of the HIV-1 Envelope Glycoprotein with CD4-Binding Site Antibodies. J Virol 90:7822-32
Rashnonejad, Afrooz; Chermahini, Gholamhossein Amini; Li, Shaoyong et al. (2016) Large-Scale Production of Adeno-Associated Viral Vector Serotype-9 Carrying the Human Survival Motor Neuron Gene. Mol Biotechnol 58:30-6
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Fuchs, Sebastian P; Martinez-Navio, José M; Piatak Jr, Michael et al. (2015) AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity. PLoS Pathog 11:e1005090
Gardner, Matthew R; Kattenhorn, Lisa M; Kondur, Hema R et al. (2015) AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519:87-91
Ahmed, Seemin S; Gao, Guangping (2015) Making the White Matter Matters: Progress in Understanding Canavan's Disease and Therapeutic Interventions Through Eight Decades. JIMD Rep 19:11-22
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

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