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Updated: Jul 24, 2026
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
AAV2/8-humanFOXP3 gene therapy shows robust anti-atherosclerosis efficacy in LDLR-KO mice on high cholesterol diet
M Cao1, S A Theus2, K D Straub3
1Central Arkansas Veterans Healthcare System, 111J, 4300 West 7th Street, Little Rock, AR, 72205, USA. MCao@uams.edu.
Abstract:
Inflammation is a key etiologic component in atherogenesis. Previously we demonstrated that adeno-associated virus (AAV) 2/8 gene delivery of Netrin1 inhibited atherosclerosis in the low density lipoprotein receptor knockout mice on high-cholesterol diet (LDLR-KO/HCD). One important finding from this study was that FOXP3 was strongly up-regulated in these Netrin1-treated animals, as FOXP3 is an anti-inflammatory gene, being the master transcription factor of regulatory T cells. These results suggested that the FOXP3 gene might potentially be used, itself, as an agent to limit atherosclerosis. To test this hypothesis AAV2/8 (AAV)/hFOXP3 or AAV/Neo (control) gene therapy virus were tail vein injected into the LDLR-KO/HCD animal model. It was found that hFOXP3 gene delivery was associated with significantly lower HCD-induced atherogenesis, as measured by larger aortic lumen cross sectional area, thinner aortic wall thickness, and lower aortic systolic blood velocity compared with Neo gene-HCD-treated controls. Moreover these measurements taken from the hFOXP3/HCD-treated animals very closely matched those measurements taken from the normal diet (ND) control animals. These data strongly suggest that AAV/hFOXP3 delivery gave a robust anti-atherosclerosis therapeutic effect and further suggest that FOXP3 be examined more stringently as a therapeutic gene for clinical use.
Insights
Gene therapy using the FOXP3 gene effectively reduced atherosclerosis in mice. This study suggests FOXP3 holds promise as a therapeutic agent for treating this cardiovascular disease.
Area of Science:
- Cardiovascular Science
- Immunology
- Gene Therapy
Background:
- Inflammation is a critical factor in the development of atherosclerosis.
- Previous research showed adeno-associated virus (AAV) mediated Netrin1 gene delivery inhibited atherosclerosis.
- Netrin1 treatment led to increased expression of FOXP3, a key anti-inflammatory gene and master regulator of T cells.
Purpose of the Study:
- To investigate the potential of FOXP3 gene therapy in limiting atherosclerosis.
- To determine if direct delivery of the FOXP3 gene could serve as an anti-atherosclerosis agent.
Main Methods:
- Adeno-associated virus serotype 2/8 (AAV2/8) carrying the human FOXP3 gene (AAV/hFOXP3) or a control gene (AAV/Neo) was administered via tail vein injection.
- The study utilized the low-density lipoprotein receptor knockout mice on a high-cholesterol diet (LDLR-KO/HCD) model.
- Atherosclerosis progression was assessed by measuring aortic lumen cross-sectional area, aortic wall thickness, and aortic systolic blood velocity.
Main Results:
- AAV/hFOXP3 gene delivery significantly reduced high-cholesterol diet-induced atherosclerosis.
- hFOXP3 treated mice exhibited larger aortic lumen cross-sectional area and thinner aortic walls compared to controls.
- Measurements in hFOXP3 treated mice closely resembled those of normal diet control animals, indicating a robust therapeutic effect.
Conclusions:
- AAV/hFOXP3 gene delivery demonstrated a significant therapeutic effect against atherosclerosis.
- FOXP3 gene therapy presents a promising strategy for combating atherosclerosis.
- Further stringent examination of FOXP3 as a clinical therapeutic gene is warranted.
