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.
|Gessler, Dominic J; Li, Danning; Xu, Hongxia et al. (2017) Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease. JCI Insight 2:e90807|
|Ai, Jianzhong; Tai, Phillip W L; Lu, Yi et al. (2017) Characterization of adenoviral transduction profile in prostate cancer cells and normal prostate tissue. Prostate 77:1265-1270|
|Li, Dongxiao; Liu, Chong; Yang, Chunxing et al. (2017) Slow Intrathecal Injection of rAAVrh10 Enhances its Transduction of Spinal Cord and Therapeutic Efficacy in a Mutant SOD1 Model of ALS. Neuroscience 365:192-205|
|Ai, Jianzhong; Li, Jia; Gessler, Dominic J et al. (2017) Adeno-associated virus serotype rh.10 displays strong muscle tropism following intraperitoneal delivery. Sci Rep 7:40336|
|Fellinger, Christoph H; Gardner, Matthew R; Bailey, Charles C et al. (2017) Simian Immunodeficiency Virus SIVmac239, but Not SIVmac316, Binds and Utilizes Human CD4 More Efficiently than Rhesus CD4. J Virol 91:|
|Gardner, Matthew R; Farzan, Michael (2017) Engineering antibody-like inhibitors to prevent and treat HIV-1 infection. Curr Opin HIV AIDS :|
|Xie, Jun; Mao, Qin; Tai, Phillip W L et al. (2017) Short DNA Hairpins Compromise Recombinant Adeno-Associated Virus Genome Homogeneity. Mol Ther 25:1363-1374|
|Davis-Gardner, Meredith E; Gardner, Matthew R; Alfant, Barnett et al. (2017) eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. PLoS Pathog 13:e1006786|
|Tang, Maoxue; Gao, Guangping; Rueda, Carlos B et al. (2017) Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein. Nat Commun 8:14152|
|Zhong, Guocai; Wang, Haimin; Li, Yujun et al. (2017) Cpf1 proteins excise CRISPR RNAs from mRNA transcripts in mammalian cells. Nat Chem Biol 13:839-841|
Showing the most recent 10 out of 34 publications