Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues

Aadil A. Khan, James T. Paget, Martin McLaughlin, Joan N. Kyula, Michelle J. Wilkinson, Timothy Pencavel, David Mansfield, Victoria Roulstone, Rohit Seth, Martin Halle, Navita Somaiah, Jessica K.R. Boult, Simon P. Robinson, Hardev S. Pandha, Richard G. Vile, Alan A. Melcher, Paul A. Harris, Kevin J. Harrington

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Improvements in cancer survival mean that long-term toxicities, which contribute to the morbidity of cancer survivorship, are being increasingly recognized. Late adverse effects (LAEs) in normal tissues after radiotherapy (RT) are characterized by vascular dysfunction and fibrosis causing volume loss and tissue contracture, for example, in the free flaps used for immediate breast reconstruction after mastectomy. We evaluated the efficacy of lentivirally delivered superoxide dismutase 2 (SOD2) overexpression and connective tissue growth factor (CTGF) knockdown by short hairpin RNA in reducing the severity of LAEs in an animal model of free flap LAEs. Vectors were delivered by intra-arterial injection, ex vivo, to target the vascular compartment. LVSOD2 and LVshCTGF monotherapy before irradiation resulted in preservation of flap volume or reduction in skin contracture, respectively. Flaps transduced with combination therapy experienced improvements in both volume loss and skin contracture. Both therapies reduced the fibrotic burden after irradiation. LAEs were associated with impaired vascular perfusion, loss of endothelial permeability, and stromal hypoxia, which were all reversed in the treatment model. Using a tumor recurrence model, we showed that SOD2 overexpression in normal tissues did not compromise the efficacy of RT against tumor cells but appeared to enhance it. LVSOD2 and LVshCTGF combination therapy by targeted, intra-vascular delivery reduced LAE severities in normal tissues without compromising the efficacy of RT and warrants translational evaluation as a free flap–targeted gene therapy.

Original languageEnglish (US)
Article numbereaar2041
JournalScience translational medicine
Volume10
Issue number425
DOIs
StatePublished - Jan 24 2018

ASJC Scopus subject areas

  • Medicine(all)

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