Cardiovascular

The United States and many other countries face a daunting challenge in the years ahead – how to deal with the consequences of a rapidly expanding population of older individuals that will require an increasing amount of healthcare intervention and resources. As we age, we become more susceptible to a variety of aging related diseases and conditions, including heart disease, stroke, vascular disease and a range of other conditions. Data from the National Center for Health Statistics shows that individuals over the age of 65 spend up to ten times as much on healthcare annually when compared to young healthy individuals – and much of this is a direct consequence of aging related diseases and conditions. Increasing rates of obesity, a significant risk factor for cardiovascular disease, stroke, diabetes and cancer, is another significant influence.

Innovative technologies like MultiStem cell therapy could enable more effective treatment of damage from cardiovascular disease, by helping to repair damage following a heart attack, and treatment of vascular disease, congestive heart failure or other conditions. We and our collaborators are focused on exploring the potential application of MultiStem to treat these and other conditions, which represent substantial areas of unmet medical need. Our first clinical study in the cardiovascular area involved administration to patients that had suffered an acute myocardial infarction.

Acute Myocardial Infarction (AMI)

AMI

Despite recent advances in cardiovascular care, myocardial infarction remains one of the leading causes of death and disability in the United States. Myocardial infarction is caused by the blockage of one or more arteries that supply blood to the heart, resulting in significant injury to the heart muscle that severely affects the patient's quality of life, or causes death. Such blockages can be caused, for example, by the rupture of an atherosclerotic plaque.

A variety of risk factors are associated with an elevated risk of myocardial infarction or atherosclerosis, including age, high blood pressure, smoking, sedentary lifestyle, and genetics. While advances in the diagnosis, prevention, and treatment of heart disease have had a positive impact, there is clearly room for improvement – myocardial infarction remains a leading cause of death and disability in the United States and the rest of the world.

Working with independent collaborators, we have evaluated MultiStem cell therapy in acute and chronic models of heart and vascular disease. These studies demonstrate that administration of MultiStem therapy promotes recovery and tissue repair through multiple mechanisms, including through promotion of angiogenesis and vasculogenesis, regulation of immune system function, and through the production of cytoprotective and cardiotropic factors. Read more about our AMI trials here.

PVD

PVD

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.

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 occurring collateral development is adversely affected 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 angiogenic factors, and currently, two clinical programs for ischemic injuries (stroke and acute myocardial infarction) are in development. In 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.

MAPCS

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.

Congestive Heart Failure

CHF

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.

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.

Our Approach

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 in 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 cell therapy with the goal of improving heart function and clinical outcome.

Treatment

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.