Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence l'intérêt, pour préserver la fonction microvasculaire et protéger les tissus sains lors d'une radiothérapie, d'utiliser conjointement deux lentivirus modifiés génétiquement, l'un exprimant la superoxyde dismutase 2 et l'autre générant un court ARN en épingle à cheveu destiné à bloquer l'expression du facteur de croissance du tissu conjonctif
With recent improvements in cancer therapy, an increasing number of people are living as cancer survivors, in many cases with long-term side effects caused by the cancer treatment. These effects include radiation-induced vascular dysfunction and fibrosis, which interfere with tissue reconstruction using skin flaps after mastectomy in breast cancer patients. Khan et al. developed a virus-based gene therapy approach to address this problem, up-regulating one gene to preserve skin flap volume and knocking down another to reduce radiation-induced skin contracture. The authors tested their approach in rat models of radiation therapy and skin flap reconstruction and also demonstrated that the gene therapy did not interfere with the anticancer effects of radiation.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.