| First Author | Hareendran S | Year | 2016 |
| Journal | Eur J Immunol | Volume | 46 |
| Issue | 1 | Pages | 154-66 |
| PubMed ID | 26443873 | Mgi Jnum | J:233871 |
| Mgi Id | MGI:5788239 | Doi | 10.1002/eji.201545867 |
| Citation | Hareendran S, et al. (2016) Synergistic inhibition of PARP-1 and NF-kappaB signaling downregulates immune response against recombinant AAV2 vectors during hepatic gene therapy. Eur J Immunol 46(1):154-66 |
| abstractText | Host immune response remains a key obstacle to widespread application of adeno-associated virus (AAV) based gene therapy. Thus, targeted inhibition of the signaling pathways that trigger such immune responses will be beneficial. Previous studies have reported that DNA damage response proteins such as poly(ADP-ribose) polymerase-1 (PARP-1) negatively affect the integration of AAV in the host genome. However, the role of PARP-1 in regulating AAV transduction and the immune response against these vectors has not been elucidated. In this study, we demonstrate that repression of PARP-1 improves the transduction of single-stranded AAV vectors both in vitro ( approximately 174%) and in vivo (two- to 3.4-fold). Inhibition of PARP-1, also significantly downregulated the expression of several proinflammatory and cytokine markers such as TLRs, ILs, NF-kappaB subunit proteins associated with the host innate response against self-complementary AAV2 vectors. The suppression of the inflammatory response targeted against these vectors was more effective upon combined inhibition of PARP-1 and NF-kappaB signaling. This strategy also effectively attenuated the AAV capsid-specific cytotoxic T-cell response, with minimal effect on vector transduction, as demonstrated in normal C57BL/6 and hemophilia B mice. These data suggest that targeting specific host cellular proteins could be useful to attenuate the immune barriers to AAV-mediated gene therapy. |
