The human heart has an innate capacity to remodel in response to advancing coronary artery disease. As plaque builds up in the heart’s three major arteries, some genetically privileged patients begin to grow small collateral blood vessels to overcome restricted blood flow and improve cardiac perfusion. This process is known as cardiac angiogenesis. With the passage of time, this response is overrun by disease progression.
Researchers have long wondered if this primal angiogenic healing response could be amplified and regulated through the design and development of angiogenic therapeutics. In recent years, monoclonal antibody therapies have proven effective at harnessing the human body’s natural biological mechanisms to treat cancer. Similarly, within cardiac care, angiogenic gene therapy has shown great promise.
In the U.S., more than one million patients with advanced coronary artery disease suffer from recurrent and severe chest pain, which profoundly limits their physical activity and quality of life. These “refractory angina” patients are no longer responsive to anti-anginal medications and are either not candidates for stent implantation or bypass surgery, or continue to suffer from angina even after these mechanical revascularization procedures. While drug and proteins appear unsuitable, new research and clinical studies focused on angiogenic gene therapy are now showing great promise as a one-time treatment for more than one million patients in the U.S. with advanced coronary artery disease and refractory angina.
The successful commercialization of an angiogenic gene therapy will require (1) an angiogenic growth factor that regulates the multiple proteins required to orchestrate micro-vessel growth and enlargement; (2) a simple percutaneous catheter-based delivery system to deliver the angiogenic gene therapy into heart cells; and (3) a deep understanding and characterization of patients who are most likely to benefit from angiogenic gene therapy, enabling design of a clinical study properly powered to detect treatment effects and assess potential risk-benefit.
Choice of Angiogenic Growth Factor
One key element of successful gene therapy is gene expression in the targeted cells, at a functional level. For angiogenic gene therapy, a central challenge has been identifying the growth factors that can stimulate the complex angiogenic biological process. It has been debated and widely studied whether the delivery of vascular endothelial growth factor (VEGF) or other growth factors, alone or in combination, is ideal for collateral vessel development. Recent research suggests a more fruitful approach may be the use of a specific regulatory gene, FGF-4, that is now known to activate VEGFs and the cascade of events required to stimulate cardiac angiogenesis. Using a regulatory gene is likely more practical than trying to determine which individual growth factor or growth factor combination is best suited for the job.
Simplified Catheter-Based Delivery Options
Even with firm understanding of the merits of individual angiogenic growth factors, a separate question remains: Which DNA delivery system is best suited for cardiovascular angiogenic gene therapy?
Advances have come with a key realization: the facilitation of coronary collateral formation requires a relatively short duration of gene expression—only a few weeks. Vector systems that meet this requirement include plasmid constructs and adenovirus. So here was the next challenge: determining which of these two approaches was optimal. Plasmids are easy to manufacture and safe but have very low level and short duration of muscle transduction and could be delivered to the heart mainly through direct intramuscular injections. Adenoviral vectors, on the other hand, can be administered via the intravascular route and have been shown to achieve high transfection efficiency in heart muscle cells with transgene expression lasting for two to six weeks. The relatively short duration of growth factor gene expression by the adenovirus serotype 5 (Ad5) vector has proved sufficient for the building of new functional biological structures such as coronary collateral vessels.
Studies have demonstrated that fibroblast growth factor-4 (FGF-4) can promote the growth of existing or new collateral vessels in the heart, when delivered as a gene within an Ad5 vector. The resulting molecular package—named Ad5FGF-4—is delivered into the heart as a one-time treatment during a standard angiogram-like procedure. The biologic is delivered in front of a balloon that briefly blocks blood flow, allowing the treatment to more easily leave the blood vessel and enter the cardiac muscle. FGF-4 gene expression promotes the development of new collateral vessels and the enlargement of existing collateral vessels in ischemic areas of the heart, to increase blood flow to these oxygen-starved regions.
Effective Clinical Study Design
An additional hindrance to historical progress in cardiovascular gene therapy may have involved study design. The standard endpoint used in most cardiovascular therapeutic angiogenesis studies—e.g., exercise tolerance testing (ETT)—is based on decades of experience with clinical development of small molecule anti-anginal drugs, and is still considered by regulatory authorities to be a relevant indicator of clinical effectiveness. In general, clinically significant improvements in ETT time resulting from mechanical revascularization (bypass surgery and stents), pharmacologic interventions or gene therapy, represent improved functional capacity for treated patients. ETT is known to be subject to placebo effect, and therefore careful study design, including well-defined patient inclusion criteria (e.g. limited baseline ETT capacity) and controlled testing conditions and criteria are essential for meaningful outcomes.
An attempt to fuse the insights and overcome the roadblocks summarized above are fueling ongoing efforts to improve and advance angiogenic gene therapy. Future studies are likely to elucidate the most promising therapies for cardiovascular angiogenic gene therapy and offer hope to the many patients for whom angina is currently a source of deep concern causing significant negative impact on quality of life.
Christopher J. Reinhard is Chief Executive Officer of Angionetics Inc., a company focused on the late-stage clinical development and commercialization of Generx®, an angiogenic gene therapy product candidate designed for medical revascularization for the potential treatment of patients with myocardial ischemia and refractory angina due to advanced coronary artery disease.
Filed Under: Drug Discovery