The story of proangiogenic gene therapy
Cardiovascular disease is one of the top killers worldwide. Heart attacks affect an estimated 275,000 people and kill 146,000 each year in the UK. A decrease in blood flow to the heart (coronary artery disease) or to the legs (peripheral artery occlusive disease), heart attack (myocardial infarction), and stroke are the most common types of cardiovascular disease. Behind these disorders lies atherosclerosis, a process in which the arteries that provide blood and, therefore, vital oxygen and nutrients to tissues and organs become "furred up" and clogged with fats and other substances.
Cholesterol-a type of fat found in foods like cheese, eggs, and poultry-plays an important role in the development of atherosclerosis. Although cholesterol is necessary for life as a building block of cell membranes or to produce hormones, high levels in the blood can cause deposits called plaques to form and accumulate inside arteries, narrowing them and obstructing blood flow to the associated organ or tissue. For example, chest pain can occur when the arteries supplying the heart with blood-the coronary arteries-are blocked.
There are several different types of treatment that can quite quickly and effectively re-open blocked arteries and restore proper blood flow inside an affected organ. In coronary bypass surgery, for example, the aim is to get around the narrowed sections of coronary arteries. Imagine taking an alternative route to get around a traffic jam when you're driving in rush hour: coronary bypass surgery works on the same principle. A blood vessel is stitched in between the main artery leaving the heart-the aorta-and a point in the coronary artery beyond the narrowed or blocked area.
Proangiogenic therapy is a new treatment option that can help restore circulation in people with blocked arteries. Angiogenesis is the formation of new blood vessels from pre-existing arteries and veins. This phenomenon can occur naturally in our bodies during wound healing, the menstrual cycle, or pregnancy, and is entirely dependent on important cellular products called angiogenic agents. Scientists are trying to use these proteins to stimulate new blood vessel formation in areas where current blood vessels are blocked in order to supply the affected area with oxygen and nutrients. A good illustration of this effect is the growth of new tree roots, which take water, nutrients, and chemicals from the soil and use them for tree growth, development, and repair.
A promising application of proangiogenic therapy seems to be via gene therapy. This method involves inserting genes into an individual's cells and tissues, which will then produce the therapeutic protein that may help to overcome a disease. A gene is only able to enter a cell when it is situated within a special carrier called a vector. Viruses possess the natural ability to bind to and introduce their genetic material into a host cell-this is how viruses infect tissues in the human body. Viral vectors have been genetically modified so that once they enter a cell, they do not produce nasty viral proteins but instead churn out therapeutic proteins-in this case, angiogenic agents that can stimulate the growth of new blood vessels.
The specific subject of my research in the Department of Medical Biotechnology at the Jagiellonian University in Krakow is the safety and efficiency of gene transfer. My studies are focused on simultaneous delivery of two or three genes encoding proteins that are important for the development of new blood vessels. Preliminary data in mice with blocked blood flow in their legs indicate that injection of two angiogenic genes that work together results in formation of stable and functional blood vessels that improves circulation in the blocked hindlimbs. At present, this strategy seems to be a promising alternative for so-called "no option patients" who are not candidates for the traditional revascularisation procedures. In the future, gene therapy might displace high risk bypass surgery and become the standard treatment for patients with atherosclerosis-related disorders.
During the past two decades, there have been a lot of successful gene therapy studies performed in animals such as mice. Similar studies performed in humans also demonstrated some positive effects. Human organs are much larger than mice organs, however, an issue that raises some technical problems regarding high efficiency gene transfer in the human body. In this regard, viral vectors seem to be the most promising gene therapy tools. Laboratories all around the world are trying to create efficient and safe carriers of genetic material.
Simultaneous delivery of two or three genes encoding proteins with complementary action that are important for the development of new blood vessels will hopefully one day allow us to decrease the risk of heart attack or limb loss in people suffering from atherosclerosis. (Agnieszka Jazwa, Jagiellonian University in Krakow, www.atomiumculture.eu)