Overview of Thoracic Aortic Dissection
Thoracic aortic dissection (TAD) is a serious cardiovascular disease characterized by a tear in the aortic intima that allows blood to flow between the inner layers of the aortic wall, forming a dissection. The disease has an acute onset, a poor prognosis and a very high mortality rate. The early clinical symptoms of TAD are not obvious and are often overlooked or misdiagnosed. Once aortic dilatation or rupture occurs, the mortality rate can be as high as 50%. Even if TAD can be detected in its early stages, there is still a lack of effective treatments in clinical practice. Intervention strategies for early TAD have therefore become a top priority for the treatment of TAD, and the development of new treatments is particularly urgent.
Gene Therapy for Thoracic Aortic Dissection
As an emerging medical method, gene therapy has attracted widespread attention in the treatment of cancer and cardiovascular diseases. Compared with traditional treatment methods, the advantage of gene therapy is that it can directly repair abnormal genes that cause diseases from the root. This treatment method can not only target the root cause of the disease, but also reduce side effects. However, the success of gene therapy depends on an effective nucleic acid delivery system. Existing gene vectors are mainly divided into viral vectors and non-viral vectors. Although viral vectors have high transfection efficiency, they have limitations such as immunogenicity, limited DNA packaging capacity and production difficulty.
Therefore, more and more researchers have begun to pay attention to the development of non-viral gene vectors. Among them, cationic gene vectors have become a research hotspot because of their easy synthesis, high stability and strong modifiability. However, traditional cationic vectors still have certain shortcomings in transfection efficiency and cytotoxicity, which seriously limit their practical application in clinical practice.
In this regard, polysaccharide materials, especially dextran, have shown good potential. Dextran, as a natural polysaccharide, has low immunogenicity, non-toxicity and excellent biocompatibility. Its molecular structure is rich in hydroxyl groups, which helps to reduce cytotoxicity, increase serum tolerance, and prolong the circulation time in the body. In addition, the multiple modifiable sites of dextran enable it to introduce multiple cationic side chains, thereby significantly enhancing the binding ability and delivery efficiency of nucleic acids. Combining these advantages, dextran has broad application prospects in gene therapy, especially in the treatment of thoracic aortic dissection, and has important clinical value.
Figure 1. Dextran-based coacervate nanodroplets as potential gene carriers. (Chenglong W, et al.; 2020)
Use of Dextran in the Treatment of Thoracic Aortic Dissection
In the narrow structure and complex physiological environment of the aortic arch, it is crucial to construct a safe, efficient and low-toxicity gene delivery system for gene therapy of thoracic aortic dissection. The study found that the carrier enrichment of different gene carriers in the thoracic aortic dissection lesions was low. Therefore, researchers are using targeting strategies to ensure that gene vectors can be efficiently delivered to the diseased area.
Studies have shown that in the early stages of TAD, before the rupture of the vascular intima and the release of medial factors, the opening of tight junctions on the intima is the earliest signal of TAD. During this process, the expression of matrix metalloproteinase-9 (MMP-9) increases significantly. This increase can cause damage to the media of the aortic wall, making the aorta fragile, increasing its diameter and ultimately leading to arterial dissection. It is known that gene silencing can be mediated by shRNA (small interfering RNA), so researchers hope to use gene therapy to reduce the expression of MMP-9 in the diseased area, thereby delaying the development of TAD and improving the condition. For this reason, dextran, as a proven molecule targeting TAD, has been used to construct a nucleic acid delivery vector for TAD gene therapy. Some researchers used dextran as the core and synthesised ethanolamine-functionalised glycidyl methacrylates (Dex-PGEAs) carrier system by atom transfer radical polymerisation and ring-opening reaction. In subsequent experiments, it was found that this dextran-based carrier can effectively carry MMP-9 and significantly reduce the incidence of dissection while maintaining good biological safety.
Conclusion
In summary, dextran has shown great application potential in gene therapy for thoracic aortic dissection. By constructing a targeted delivery system, dextran can not only effectively reduce the expression of MMP-9 and delay the progression of TAD, but also improve the overall efficiency of gene therapy and reduce cytotoxicity. The related research result provides new ideas for the treatment of thoracic aortic dissection and may play an important role in future clinical practice. With the continuous development of related technologies, the application prospects of dextran in the field of gene therapy will be broader and worthy of further in-depth research and exploration.
References
- Chenglong W, et al.; Dextran-based coacervate nanodroplets as potential gene carriers for efficient cancer therapy. Carbohydr Polym. 2020, 231:115687.
- Xu C, et al.; Multifunctional cationic nanosystems for nucleic acid therapy of thoracic aortic dissection. Nat Commun. 2019, 10(1):3184.
- Yang X, et al.; Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection. Eur Heart J. 2023, 44(14):1248-1261.
