TY - JOUR
T1 - Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues
AU - Khan, Aadil A.
AU - Paget, James T.
AU - McLaughlin, Martin
AU - Kyula, Joan N.
AU - Wilkinson, Michelle J.
AU - Pencavel, Timothy
AU - Mansfield, David
AU - Roulstone, Victoria
AU - Seth, Rohit
AU - Halle, Martin
AU - Somaiah, Navita
AU - Boult, Jessica K.R.
AU - Robinson, Simon P.
AU - Pandha, Hardev S.
AU - Vile, Richard G.
AU - Melcher, Alan A.
AU - Harris, Paul A.
AU - Harrington, Kevin J.
N1 - Publisher Copyright:
Copyright © 2018 The Authors, some rights reserved.
PY - 2018/1/24
Y1 - 2018/1/24
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aar2041
DO - 10.1126/scitranslmed.aar2041
M3 - Article
C2 - 29367346
AN - SCOPUS:85041197829
SN - 1946-6234
VL - 10
JO - Science translational medicine
JF - Science translational medicine
IS - 425
M1 - eaar2041
ER -