Targets

Therapeutic Targets

The main target of our therapies is reverse cholesterol transport (RCT). This is the mechanism of removing cholesterol from peripheral tissues and shuttling it back to the liver for removal from the body and/or recycling. The lipoprotein that accomplishes this is high density lipoprotein (HDL), the “good” cholesterol. The essential protein involved in this process is apolipoprotein A-I (apo A-I), which initiates the formation of HDL. The study of apo A-I has been mostly intensified around its ability to remove cholesterol from atherosclerotic plaques in patients with coronary artery disease. This has been further bolstered by epidemiologic data that suggests that heart disease risk is inversely proportional to HDL cholesterol (HDL-C) levels, meaning the higher your HDL-C the lower your heart disease risk (and vice versa). Please see the video below for a basic animation of the RCT pathway.

Supplement from this article: JAMA. 2007;298(7):786-798.

Interestingly but not surprisingly, RCT is important in many other disease processes as well. The action of removing cholesterol from cell membranes plays an important role in neurologic disease, autoimmunity and tumor survival. Since the pathway begins with apo A-I, we have focused on improving biologic apo A-I therapies to make an impact on many potential diseases. We have created a new way to combine apo A-I with rescue enzymes to improve the overall benefits and applicability of the treatments.

How is RCT and/or apo A-I involved in the diseases below?

Atherosclerosis
As mentioned above, apo A-I and HDL can remove cholesterol from atherosclerotic plaques, which can build up in coronary arteries and carotid arteries of the neck. Plaque formation increases the risk for heart attack and stroke. The process of RCT (reversal of plaque formation) can be rendered dysfunctional by many different mechanisms, including oxidation of apo A-I and altered protein composition of HDL. Improving the RCT pathway is a highly desirable target to reduce cardiovascular disease, the number one cause of death in the world.
Autoimmune Disease
The anti-inflammatory properties of apo A-I have been well documented. The RCT pathway modulates immune response by removing cholesterol from cell membranes and reducing expression of inflammatory cytokines. Cholesterol accumulation in antigen presenting cells has been shown to promote development of autoimmunity in animal models. Apo A-I is also damaged by oxidative stress and is dysfunctional in patients with rheumatoid arthritis and lupus. This suggests that increasing the RCT pathway may be beneficial in autoimmune diseases such as rheumatoid arthritis and lupus.
Neurologic Disease
Alzheimer’s disease (AD) is characterized by deposition of β-amyloid peptides that form plaques in the brain. Apo A-I is readily transported to the brain and can inhibit deposition and aggregation of these peptides to decrease plaque formation. Lower levels of apo A-I have also been found in patients with Parkinson’s disease, suggesting a role for it in this process.
Cancer
Multiple models have shown potent anti-tumor activity of apo A-I. It positively affected immunomodulation by increasing anti-tumor activity of killer T cells (CD8+) and macrophage phenotype changes that aided in rejecting tumors. It also reduced angiogenesis (new blood vessel formation) which is necessary for tumor survival and growth. Apo A-I reduced MMP-9 activity which is an extracellular matrix degrading enzyme that is needed for tumors to spread to distant sites. Overall, apo A-I creates a hostile environment for tumors.

Rescue Enzymes

Our targets not only involve the RCT pathway, but we combine the benefit of RCT with other pathways to provide a "rescue" therapy. The concept of a rescue enzyme involves one that can rescue the body following a toxic insult. One pathway we have focused on is mediated by the paraoxanase-1 (PON-1) enzyme. This enzyme is an antioxidant that reduces oxidized LDL thereby reducing atherosclerosis. It also hydrolizes organophosphates and detoxifies substances such as pesticides and nerve gases. A pon-1 gene allele is associated with increased risk for development of Parkinson's disease after exposure to organophosphates. We are studying novel approaches for combining and enhancing apo A-I with PON-1 activity.

The goal of this strategy is to provide a molecule that contains the beneficial aspects of HDL, apo A-I and PON-1, in a fused protein as a single therapeutic agent. Under inflammatory conditions and oxidative stress, nascent HDL can be rendered dysfunctional. Our approach provides extra and enhanced apo A-I and PON-1 which can result in reduced inflammation and improved anti-oxidant effects. When conjoined, these proteins can provide a powerful means of reducing and liberating atherosclerotic plaque and removing it from the body. Also, apo A-I can then deliver PON-1 to the brain as it is readily transported there. It can provide therapy that can rescue high risk patients with atherosclerosis and neurodegenerative disease.

A beacon for those in need of rescue therapies