|
|
|
Peripheral vascular disease (PVD), which is sometimes referred to as peripheral arterial disease (PAD), is characterized by chronic poor blood flow in the lower extremities, which can cause pain, ischemic lesions or ulcers, and sepsis. Over time this condition can progress to critical limb ischemia, and eventually lead to limb amputation. According to the 2010 American Heart Association annual statistical report on heart disease, approximately 8 million Americans have peripheral vascular disease (PVD), and suffer significant morbidity and mortality as a result. In 2004 the direct and indirect costs of treating PVD were estimated to be over $2 billion dollars annually in the United States alone.
Current treatment of PVD depends on the severity of the disease. Current approaches include treatment to reduce risk factors, drug therapy to reduce clotting and plaque formation, or surgical intervention in an attempt to revascularize the region of ischemic damage. However, many of the approved pharmaceutical interventions have significant side effects, and many patients are unfit candidates for revascularization due to advanced age, advanced ischemia or the presence of other complicating conditions. Additionally, revascularization is only successful 44% of the time.
Recent studies suggest that an increase in the collateral vascular network may offer protection from ischemic episodes. Collaterals normally form, remodel and enlarge around the site of blockage allowing blood flow to bypass the occluded artery and allow perfusion of the ischemic tissue. However, naturally occuring collateral development is adversely affect by age, hypercholesterolemia, diabetes and smoking and is insufficient to support adequate blood flow to the affected tissues in many PVD patients, especially during exertion.
Given that the vascular growth process requires coordination of a complex array of molecular mechanisms, we believe that the targeted delivery of multiple protein factors that can promote angiogenesis and protect and repair ischemic tissue could be an effective approach to enhance healing of ischemic tissue. The dynamic and responsive nature of MultiStem®, and the ability to express multiple factors that can influence the healing and tissue repair process makes it an attractive cellular therapy addition to current therapies. MultiStem has been shown to secrete multiple angiogenic factors and currently, two clinical trials for ischemic injuries, stroke and acute myocardial infarction, are being initiated or are ongoing. In multiple animal models of PVD, MultiStem treatment has resulted in significant improvement in blood flow, vessel density, muscle function, and stimulated muscle regeneration. Even in models of severe limb ischemia, as evidence by increased tissue necrosis, treatment with these cells expanded the collateral bed by 21 days and showed improvement in muscle function and a decrease in toe necrosis and limb loss compared to vehicle treated controls. We intend to leverage this preclinical data and related preclinical and clinical data from other programs to move into clinical development as resources and opportunities permit, or as part of a business partnership.
Figure: Administration of human MAPCs in a rodent model of peripheral vascular ischemia results in significantly improved blood flow in the hind limb region by day 30 relative to control animals treated with PBS. Images from Aaranguren et al Cell Transplant. 2011;20(2):259-69.
|
|
|
|
|
|
|
Heart Failure is a progressive disease that is defined as an in ability of the heart to provide adequate blood flow throughout the body due to damage of the heart tissue. When the heart is unable to keep up with the normal demands required to pump blood, remodeling occurs to compensate for the heart’s decreased function. Remodeling includes enlargement of the heart, increased muscle mass and wall thickening, and increased heart rate. Symptoms of heart failure include fluid collection in tissues and lungs, shortness of breath and fatigue. The causes of heart failure are varied and can include coronary heart disease, high blood pressure, diabetes, cardiomyopathy, heart valve disease, arrhythmias, and congenital heart defects.
Currently, there is no cure for heart failure. According to the American Heart Association, heart failure affects 2% of the population and causes 300,000 deaths each year in the Unites States alone. In 2008, the estimated total cost of heart failure in the United States was $37.2 billion dollars.
Heart failure is a chronic and progressive disease that requires lifelong management. Treatments include pharmaceutical management, lifestyle changes and risk factor reduction. Medications include vasodilators such as ACE inhibitors and Angiotenson II receptor blockers, beta blockers to decrease heart rate and blood pressure, diuretics to prevent fluid buildup, and aldosterone antagonists to improve heart function. More severe cases required surgical procedures to prevent further tissue damage. However, many patients continue to worsen despite these interventions, and there is a high rate of mortality associated with the condition.
Given that heart failure is often caused by damage to the heart tissue due to reduced blood flow and oxygen supply, an increase in blood supply to the heart tissue would help prevent further tissue damage and progression of the disease. MultiStem has shown benefit in preclinical models of cardiovascular disease, demonstrating an ability to promote formation of new blood vessels, reduce local and systemic inflammatory activity and protect cells and tissue and the region of damage. We believe that multiple factors produced by the cells could provide benefit to heart failure patients, through improved blood flow and may assist in the reversal of remodeling. In addition, an “off the shelf” product may provide benefit for heart failure patients who may be too compromised to undergo an autologous bone marrow draw. Building on our experience in acute myocardial infarction, our strategic goal is to develop a clinical program to treat ischemic heart failure patients with MultiStem with the goal of improving heart function and clinical outcome.
Figure: Treatment with allogeneic MultiStem increased vessel density in the border region of the infarct zone in a rat model of heart failure at 4 weeks compared to control animals. Vessel density was determined by the number of VWF staining vessels (in green) per mm2
|
|
|
|
|
|