Abstract 4162: Lentivirally delivered shRNA knockdown of CXCL12 is effective at preventing radiation fibrosis in normal tissues

Late Adverse Effects (LAEs) following adjuvant radiotherapy (RT) are common sequelae in free flaps used for breast reconstruction and result in ongoing healthcare burdens during the phase of cancer survivorship. Intra-arterial delivery of gene therapy to an isolated vascular region permits localized, targeted genetic modulation of reconstructed tissue, avoiding potential off-target effects in microscopic residual disease. We studied the immunological component of LAE development in a validated accelerated rodent model recapitulating autologous flap reconstruction, across 90 days after RT (50 Gy/3). CXCL12 was significantly up-regulated from 2-21 days after RT, peaking at 7 days (p We hypothesized that LAEs in animals with flap-targeted knockdown of CXCL12 would be reduced. Flaps were infected with vascularly-delivered, lentiviral particles encoding shRNA against CXCL12 (LVshCXCL12), scrambled controls (LVSCR) alongside sham (phosphate-buffered saline (PBS)) and un-irradiated controls. Flaps infected with LVshCXCL12 exhibited reversal of LAE-mediated flap contracture and were not significantly different from un-irradiated flaps at 90 days post-RT, but were significantly greater in area compared to sham flaps or those infected with LVSCR (p In conclusion, targeted knockdown of CXCL12 is effective at preventing the development of LAEs in flap tissue exposed to RT and is a promising strategy for clinical translation. Citation Format: James T. Paget, Martin McLaughlin, Joan N. Kyula, David Mansfield, Henry G. Smith, Victoria Roulstone, Paul A. Harris, Alan A. Melcher, Kevin J. Harrington, Aadil A. Khan. Lentivirally delivered shRNA knockdown of CXCL12 is effective at preventing radiation fibrosis in normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4162.