Obstructions to blood flow in the vessels of the heart and the legs are the most common cause of death and disability in the western world. The aim of our studies is to develop strategies to grow new blood vessels to improve the flow in diseased areas. To do this we will deliver the genetic information for two substances which control the induction of new blood vessels (VEGF) and their stabilization (PDGF) into the muscle of mice. The working hypothesis is that PDGF can modulate the effects of VEGF and increase both its efficacy and safety. Delivering the genetic information, rather than the substances themselves, will ensure that they are continously produced directly in the diseased tissue, without loss of therapeutic levels.
We will determine the effects of VEGF and PDGF co-expression in skeletal muscle at different doses, both in terms of vessel quantity and quality, and of appearance of toxic effects. This will define the therapeutic window for their combined expression (Aim 1). We will then determine the time over which expression of the 2 genes must be continued in order to achieve proper stabilization and persistence of the induced vessels (Aim 2). For technical reasons, these experiments will use muscle precursor cells genetically-engineered to express defined levels of each of the two substances. In the last aim, we will test the feasibility of delivering the genetic information directly to muscle tissue, without using cells, as a novel gene therapy strategy to achieve safe and efficacious blood vessel growth. This method would be more directly applicable to clinical practice (Aim 3).
Our proposed research is motivated by the demand for improved treatment options for patients affected by ischemic cardiovascular diseases. The latest available statistics reveal that coronary artery disease affected 13 million people and peripheral artery disease 8 million in the USA in 2003 (American Heart Association website: www.americanheart.org/statistics). There is no medical therapy to halt or revert the process of atherosclerotic vessel obstruction. Surgery is often not feasible because of diffuse vessel disease or inacceptably high operative risk. Moreover, these long-lasting conditions have huge economic burdens for society, both in terms of lost productivity and healthcare costs. The American Heart Association estimates the total costs for coronary artery disease alone in 2006 at 142 billion dollars in the USA. The proposed research is expected to define the basic parameters necessary to assess the therapeutic potential of VEGF and PDGF co-delivery: dose, duration and toxic effects. This knowledge is a prerequisite for the development of novel therapeutic angiogenesis strategies which could be applied to a large number of patients suffering from these diseases.