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Gene therapy for atherosclerosis
1Department of Medicine, University of Pennsylvania Health System, Philadelphia 19104-6100, USA.
Abstract:
Although considerable progress has been made in the prevention and treatment of atherosclerotic cardiovascular disease, new therapeutic strategies are still needed. Atherosclerosis is a systemic disease and represents an attractive target for the development of somatic gene transfer intended to modulate systemic factors with the goal of inhibiting disease progression. This approach should be differentiated from localized vascular gene delivery to isolated atherosclerotic lesions such as that intended to prevent restenosis. Systemic gene therapy for atherosclerosis can involve either: 1) gene replacement therapy in patients with defined genetic disorder causing premature atherosclerosis, or 2) overexpression of proteins which directly or indirectly inhibit atherosclerosis or stabilize vulnerable lesions. The former is conceptually straightforward, and a pilot clinical gene therapy trial for one of these diseases, homozygous familial hypercholesterolemia, has already been reported. The latter has significant potential for eventual application to a large number of patients at risk for progressive atherosclerosis, independent of the specific cause. However, substantial progress in vector development and the demonstration of efficacy in relevant animal models will be required before gene therapy for atherosclerosis becomes a clinical reality.
Insights
New gene therapy strategies show promise for treating atherosclerosis, a systemic cardiovascular disease. While gene replacement is established for specific genetic disorders, protein overexpression offers broader potential for inhibiting disease progression.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Molecular Biology
Background:
- Atherosclerotic cardiovascular disease remains a significant health concern despite advances in prevention and treatment.
- Atherosclerosis is a systemic condition, making it a suitable target for systemic gene therapy approaches.
- Current therapeutic strategies necessitate the development of novel approaches to inhibit disease progression.
Purpose of the Study:
- To explore the potential of somatic gene transfer as a therapeutic strategy for atherosclerosis.
- To differentiate systemic gene therapy from localized vascular gene delivery for atherosclerotic lesions.
- To outline two primary strategies for systemic gene therapy in atherosclerosis: gene replacement and protein overexpression.
Main Methods:
- Review of existing literature and clinical trials in gene therapy for cardiovascular diseases.
- Conceptual framework for systemic gene therapy targeting atherosclerosis.
- Identification of potential targets and challenges for gene therapy application.
Main Results:
- Gene replacement therapy is feasible for genetic disorders causing premature atherosclerosis, with a pilot trial for homozygous familial hypercholesterolemia reported.
- Protein overexpression strategies hold potential for broad application in patients at risk for atherosclerosis, independent of etiology.
- Systemic gene therapy requires further advancements in vector development and validation in animal models.
Conclusions:
- Systemic gene therapy presents a promising avenue for treating atherosclerosis by modulating systemic factors.
- Further research and development, particularly in vector technology and preclinical efficacy, are crucial for clinical translation.
- Gene therapy offers a potential future therapeutic modality for a large patient population at risk for progressive atherosclerosis.