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Updated: May 25, 2026
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
BRCA1 gene therapy reduces systemic inflammatory response and multiple organ failure and improves survival in
H Teoh1, A Quan, A K Creighton
1Division of Cardiac Surgery, St Michael's Hospital, Toronto, ON, Canada. teohh@smh.ca
Abstract:
Sepsis-related complications and mortality remain a major clinical problem. Increased cell death and unresolved cellular repair have been implicated as key upstream mediators of sepsis-induced organ dysfunction and death. We hypothesised that gene therapy with BRCA1, a critical regulator of DNA damage repair and cell survival, would attenuate the sequelae of sepsis and peritonitis in mice subjected to caecal ligation and perforation (CLP) and thioglycollate stimulation. C57Bl/6J mice underwent sham or CLP surgery 3 days following treatment with either human BRCA1 adenovirus (AdBRCA1) or the adeno-CMV-null vector (Adnull). The 24-h post-CLP mortality was 2.8% vs 17.9% (P<0.001) and the median post-CLP survival was 50.5 vs 33 h (P<0.05) for AdBRCA1- vs Adnull-treated mice, respectively. AdBRCA1 therapy blunted CLP-associated cardiac, pulmonary, hepatic and renal dysfunction and also reduced CLP-elicited double strand breaks and apoptosis in the liver. BRCA1 gene therapy was associated with lower CLP-evoked cardiac and hepatic superoxide generation that in the liver was in part due to improved reactive oxygen species removal. CLP also elevated mesenteric arteriolar and serum intercellular adhesion molecule-1, both of which were partially abrogated with AdBRCA1 administration. Thioglycollate-challenged AdBRCA1-treated mice displayed reduced peritoneal neutrophil recruitment and dampened cytokine elaboration relative to their Adnull-treated counterparts. Taken together, we report a novel role of BRCA1 gene therapy in limiting systemic inflammation, multiple-organ failure and mortality in experimental sepsis.
Insights
BRCA1 gene therapy significantly reduced mortality and organ dysfunction in mice with experimental sepsis. This approach offers a novel strategy for treating sepsis by enhancing DNA repair and cell survival.
Area of Science:
- Molecular Biology
- Genetics
- Immunology
Background:
- Sepsis causes significant mortality and organ dysfunction, linked to cell death and impaired repair.
- BRCA1 is crucial for DNA damage repair and cell survival, suggesting a potential therapeutic role.
Purpose of the Study:
- To investigate the efficacy of BRCA1 gene therapy in mitigating sepsis-induced complications and mortality in a mouse model.
Main Methods:
- Mice underwent caecal ligation and perforation (CLP) or thioglycollate stimulation.
- Mice were treated with human BRCA1 adenovirus (AdBRCA1) or a control vector (Adnull).
- Organ function, DNA damage, apoptosis, oxidative stress, and inflammatory markers were assessed.
Main Results:
- AdBRCA1 treatment reduced 24-h mortality (2.8% vs 17.9%) and increased median survival (50.5 vs 33 h) post-CLP.
- BRCA1 therapy attenuated cardiac, pulmonary, hepatic, and renal dysfunction, and reduced DNA damage and apoptosis in the liver.
- AdBRCA1 decreased oxidative stress, intercellular adhesion molecule-1 levels, and peritoneal neutrophil recruitment and cytokine release.
Conclusions:
- BRCA1 gene therapy demonstrates a novel therapeutic potential in limiting systemic inflammation, multiple-organ failure, and mortality in experimental sepsis.
- Targeting DNA repair mechanisms with BRCA1 offers a promising strategy for sepsis treatment.
