Promising Initial Results From a Phase II Trial of VEGF Gene Therapy

Intravenous, high-dose AAV gene therapy to upregulate VEGF has been shown to extend life in mice. This is perhaps a demonstration of the importance of loss of capillary density in tissue as a result of age-related disruption to angiogenesis, the multi-step process by which new blood vessels branch from existing vessels. Upregulation of VEGF is one of the possible approaches to restoring maintenance of capillary networks via improved angiogenesis, as VEGF is one of the important signal molecules involved in this process.

A similar AAV gene therapy is being assessed in clinical trials for the treatment of coronary artery disease, the progressive blockage of blood flow to heart tissue by atherosclerotic plaque. Preliminary results were recently announced for the EXACT phase II trial. The idea here is to incrementally improve blood flow by encouraging the body to produce alternative paths. The therapy is locally delivered to heart tissue, and thus uses a much lower dose than would be needed for intravenous injection for delivery to much of the body. Nonetheless, the principle is much the same. One could argue that all older individuals would likely benefit from some form of VEGF upregulation delivered to much of the body.

Gene therapy treatment increasing body's signal for new blood vessel growth shows promise

Final 12-month data from the EXACT trial demonstrates safety and efficacy results for a vascular endothelial growth factor (VEGF) gene therapy treatment for patients who have advanced coronary artery disease (CAD). CAD, also known as coronary heart disease or ischemic heart disease, affects about 20.5 million U.S. adults - making it the most common type of heart disease in the United States. Often, the first sign of CAD is a heart attack, triggered by a rupture of plaque accumulated in the arteries supplying blood to the heart. Over time, plaque narrows these arteries, blood flow diminishes, leading to angina - a condition characterized by chest pain due to insufficient oxygen-rich blood supply to the heart muscle. In patients with the most severe form, angina can be disabling, and additional medications, procedures or surgery may not be effective. There is a need for therapies for such a serious condition.

The EXACT trial assesses the safety and preliminary efficacy of the gene therapy XC001 in patients with "no option" refractory angina (NORA). The gene vector is designed to more effectively and safely increase the body's own signal for new blood vessel growth. Effectiveness was measured primarily by exercise capacity, degree of impairment of blood flow to the heart, and angina frequency and severity. Among the 32 patients with NORA, the gene therapy XC001 appeared safe with no serious adverse effects due to the drug. Surgical delivery was generally well-tolerated. Early benefits of XC001 are promising in relation to improvements in exercise duration, decreased symptoms, and improved blood flow in patients' hearts.

Total exercise duration increased from a mean of 359.9 seconds at baseline to 448.2 at three months, 449.2 at six months, and 477.6 at 12 months. Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% at three months, 14.3% at six months, and 10.2% at 12 months - demonstrating a reduction in impaired blood flood. The time to onset of ST depression during exercise tolerance testing increased by 105.2 at three months, 113.6 at six months, and 103.1 seconds at 12 months. Angina frequency decreased by -7.7 at three months, -6.6 at six months, and -8.8 episodes at 12 months. Angina class improved in 81% of participants at six months.

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