Mitigation of radiation‐induced skin injury by AAV2‐mediated MnSOD gene therapy

Yan, Shaohua; Brown, Stephen L.; Kolozsvary, Andrew; Freytag, Svend O.; Lü, Mei; Kim, Jae Ho

doi:10.1002/jgm.1226

Cited by 29 publications

(26 citation statements)

References 40 publications

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“…These results indicate the marked relief of IR-induced skin injury provided by Mn-SOD expression (32). Because of the high radiosensitivity, it is obvious that hematopoietic cell proliferation can be suppressed upon the exposure to radiation (33).…”

Section: Radioprotection At the Tissue Or Organ Levelmentioning

confidence: 73%

Research progress in the radioprotective effect of superoxide dismutase

et al. 2012

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Irradiation from diverse sources is ubiquitous and closely associated with human activity. Radiation therapy (RT), an important component of the multiple radiation origins, contributes significantly to oncotherapy by killing tumor cells. On the other hand, RT can also cause some undesired normal tissue injuries that afflict numerous cancer patients. Although many promising radioprotective agents are emerging, few of them have entered the market successfully due to various limitations. At present, the most accepted hypothesis for the radiation-caused injury involves reactive oxygen species (ROS) generation. Superoxide dismutase (SOD), the unique enzyme responsible for the dismutation of superoxide radicals, is expected to occupy an indispensable position in the treatment of ROS-mediated tissue injuries originating from exposure to radiation. This review focuses on the mechanism of radioprotection by SOD at the tissue or organ level, cellular level, and molecular level, respectively, in order to provide references for further investigation of radiation injury and development of new radioprotectors.

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Section: Radioprotection At the Tissue Or Organ Levelmentioning

confidence: 73%

Research progress in the radioprotective effect of superoxide dismutase

et al. 2012

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“…It has been estimated that 66% of damage caused by radiation is due to free radicals generated during radiation and that 33% of the damage results from persistent postirradiation oxidative stress (63). Given the known bioactivity of the SOD mimetics and the postirradiation administration of the drugs, we think it is highly unlikely that these compounds reduce direct radiation-induced DNA damage but that instead it is likely that they reduce the activity of long-lived radicals and scavenge new radicals generated by secondary biochemical events hours to days after irradiation.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies conducted in vitro and in vivo have demonstrated that several agents can increase survival of cells or animals when administered after exposure to lethal doses of radiation (30–32). For example, lethally irradiated embryonic cells treated up to 1 h postirradiation with a nitroxide, hemigramicidin-TEMPO, had significantly improved clonogenic survival (30).…”

Section: Introductionmentioning

confidence: 99%

“…A fungus, Hirsutella sinensis (CorImmune), administered 2 h after lethal total-body irradiation (TBI) of BALB/c mice resulted in survival of more than half the mice, whereas all of the vehicle-treated mice died (31). After treatment of mice with 35 Gy, a subcutaneous injection of an adenovirus vector overexpressing manganese SOD significantly mitigated both acute and chronic radiation-induced skin damage (32). Another class of Mn-based SOD mimetic reduced micronucleus formation when given by intraperiteneal injection hours after irradiation in a rat model of lung pneumonitis but did not improve survival of rats (33).…”

Section: Introductionmentioning

confidence: 99%

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Novel Synthetic SOD/Catalase Mimetics Can Mitigate Capillary Endothelial Cell Apoptosis Caused by Ionizing Radiation

et al. 2010

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Numerous in vitro and in vivo studies have shown that the endothelial cells of the microvasculature of the lung and kidney are damaged by exposure to ionizing radiation, and this sustained endothelial cell injury is involved in the early and late radiation effects observed in these tissues. It is well accepted that ionizing radiation causes the generation of reactive oxygen species during exposure that results in damage to DNA and cellular organelles. It is more controversial, however, whether additional biochemical events or long-lived radicals occur and persist postirradiation that amplify and initiate new forms of cellular damage. Two families of Eukarion (EUK) compounds have been synthesized that possess superoxide dismutase (SOD), catalase and peroxidase activities. The Mn porphyrins are available orally whereas the salen Mn complexes are administered by injection. In the present study we have examined the ability of these SOD/catalase mimetics to prevent apoptosis of endothelial cells when administered 1 h postirradiation (mitigation). A range of salen Mn complex (EUK-189 and EUK-207) and Mn porphyrins (EUK-418, -423, -425, -450, -451, -452, -453) were used to treat endothelial cells 1 h after the cells received 2–20 Gy ionizing radiation in vitro. Two lead compounds, EUK-207 at a dose of 30 μM and EUK-451 at a dose of 10 μM, exhibited low toxicity and mitigated radiation-induced apoptosis. Future animal studies will test whether these compounds protect when administered after radiation exposure as would be done after a radiological accident or a terrorism event.

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“…For example adeno-associated virus (AAV), first used in 1984 [15][16][17], is known to actively express transduced genes for 22 months in mice and 10 years in humans [18,19]. Gene delivery/gene therapy, utilizing a variety of virus types, has delivered antioxidant genes into cells and animals, however most of these studies have limited to the delivery of various forms of SOD or catalase [20][21][22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Systemic Delivery of Thiol-Specific Antioxidant hPRDX6 Gene by AAV2/8 Inhibits Atherogenesis in LDLR KO Mice on HCD

Zhu¹,

Cao²,

Kd³

et al. 2013

J Genet Syndr Gene Ther

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Atherosclerosis is an inflammatory disorder of arteries and reactive oxygen species (ROS) have been implicated as a major etiology. Various anti-ROS genes, such as superoxide dismutates and catalase, have been studied by gene transfer for their abilities to limit a variety of ROS-related cardiovascular injuries such as balloon-induced and ischemia-reperfusion injury. However the thiol-ROS compartment has never been explored by gene therapy/ gene delivery for potential therapeutic intervention. Human peroxiredoxin 6 (hPRDX6, AOL2) is fully unique in that in addition to its thiol-specific anti-oxidant ability it has a coupled phospholipase A2 catalytic domain. Here we delivered hPRDX6, expressed by the cytomegalovirus immediate early promoter (CMV), by systemic pseudotyped adeno-associated virus 2/8 (AAV2/8) gene transfer into low density lipoprotein receptor knockout mice on high cholesterol diet (LDLR KO HCD). It was found that AAV2/8/hPRDX6 gene delivery and expression inhibited systolic blood velocity, aortic cross sectional area, and aortic wall thickness compared to Neo-HCD control, consistent with reduced atherosclerosis. Markers of macrophages/foam cells, CD68, ITGAM, EMR, verified lower atherosclerosis, as all were lower in the AAV8/hPRDX6-HCD-treated animals compared to Neo-HCD controls, analyzed by either quantitative reverse transcriptase polymerase chain reaction amplification or by immuno-histochemistry, or both. Analysis of the immune state of the aortas (Th1 or Th2 cytokine expression) revealed nothing significant, with only IL-10 expression being lower in PRDX6-treated animals. This study, for the first time, demonstrated that hPRDX6 gene delivery, augmenting endogenous mouse (m)PRDX6 expression, giving therapeutic benefit against HCDdriven atherosclerosis and suggests further studies of PRDX6, and related anti-thiol-ROS approaches, is warranted.

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Mitigation of radiation‐induced skin injury by AAV2‐mediated MnSOD gene therapy

Abstract: The proof-of-concept demonstrated in the present study together with the known safety profile in humans indicate that AAV-mediated MnSOD expression has potential countermeasure utility against normal tissue injury following radiation therapy or radiological accident.

Cited by 29 publications

References 40 publications

Research progress in the radioprotective effect of superoxide dismutase

Research progress in the radioprotective effect of superoxide dismutase

Novel Synthetic SOD/Catalase Mimetics Can Mitigate Capillary Endothelial Cell Apoptosis Caused by Ionizing Radiation

Systemic Delivery of Thiol-Specific Antioxidant hPRDX6 Gene by AAV2/8 Inhibits Atherogenesis in LDLR KO Mice on HCD

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