Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues.
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Date
2018-01-24ICR Author
Author
Khan, AA
Paget, JT
McLaughlin, M
Kyula, JN
Wilkinson, MJ
Pencavel, T
Mansfield, D
Roulstone, V
Seth, R
Halle, M
Somaiah, N
Boult, JKR
Robinson, SP
Pandha, HS
Vile, RG
Melcher, AA
Harris, PA
Harrington, KJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Surgical Flaps
Mitochondria
Endothelial Cells
Skin
Animals
Rats, Inbred F344
Humans
Lentivirus
Radiation Injuries
Fibrosis
Superoxide Dismutase
Magnetic Resonance Imaging
Reproducibility of Results
Cell Death
Phenotype
Transgenes
X-Rays
Male
Connective Tissue Growth Factor
Microvessels
HEK293 Cells
Genetic Therapy
Research team
Pre-Clinical MRI
Targeted Therapy
Translational Breast Radiobiology
Translational Immunotherapy
Language
eng
Date accepted
2017-11-08
License start date
2018-01
Citation
Science translational medicine, 2018, 10 (425)
Publisher
AMER ASSOC ADVANCEMENT SCIENCE