Tissue-type plasminogen activator gene targets thrombolysis in atriums

Area of Science:

• Biomedical Engineering
• Gene Therapy
• Cardiovascular Research

Background:

• Previous studies demonstrated retroviral gene transfer of tissue-type plasminogen activator (tPA) for effective thrombolysis.
• Mechanical heart valves, often using Dacron components, are susceptible to thrombus formation.
• Developing strategies to prevent thrombosis around implanted devices is crucial for patient outcomes.

Purpose of the Study:

• To evaluate the efficacy of retroviral vector-mediated tPA gene transfer in preventing thrombus formation on Dacron patches implanted in the left atria of rabbits.
• To assess the local expression, activity, and thrombolytic effect of tPA delivered via gene therapy.

Main Methods:

• Dacron patches were implanted in the left atria of 70 New Zealand white rabbits.
• Rabbits were divided into three groups: gene therapy (pLEGFP-N1-tPA), control (pLEGFP-N1), and blank control (DMEM + NCS).
• Thrombus formation, EGFP expression, and tPA levels/activity were assessed using microscopy, Western blot, ELISA, and plasma plate assays at 2 and 75 days post-surgery.

Main Results:

• No thrombus formation was observed on Dacron patches in the tPA gene therapy group.
• High levels and activity of tPA were detected in the local left atrial tissue and blood.
• Gene therapy resulted in rapid, efficient, and sustained thrombolysis.

Conclusions:

• Local retroviral gene transfer of tPA effectively prevents thrombus formation on Dacron patches in the left atrium.
• This approach offers a promising foundation for developing a tPA gene valve for mechanical valve replacement.
• Sustained tPA expression and activity contribute to effective thrombolysis in a relevant preclinical model.