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

Khan, Aadil A., Paget, James T., McLaughlin, Martin, Kyula, Joan N., Wilkinson, Michelle J., Pencavel, Timothy, Mansfield, David, Roulstone, Victoria, Seth, Rohit, Halle, Martin , Somaiah, Navita, Boult, Jessica K. R., Robinson, Simon P., Pandha, Hardev, Vile, Richard G., Melcher, Alan A., Harris, Paul A. and Harrington, Kevin J. (2018) Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues Science Translational Medicine, 10 (425).

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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, intravascular delivery reduced LAE severities in normal tissues without compromising the efficacy of RT and warrants translational evaluation as a free flap–targeted gene therapy.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Khan, Aadil A.
Paget, James T.
McLaughlin, Martin
Kyula, Joan N.
Wilkinson, Michelle J.
Pencavel, Timothy
Mansfield, David
Roulstone, Victoria
Seth, Rohit
Halle, Martin
Somaiah, Navita
Boult, Jessica K. R.
Robinson, Simon P.
Vile, Richard G.
Melcher, Alan A.
Harris, Paul A.
Harrington, Kevin J.
Date : 24 January 2018
DOI : 10.1126/scitranslmed.aar2041
Copyright Disclaimer : Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Depositing User : Clive Harris
Date Deposited : 02 Feb 2018 10:10
Last Modified : 25 Jul 2018 02:08

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