Assay Objectives

Synvista is developing a diagnostic assay for CML that it believes can be used to determine which patients are at risk for aortic stiffness and its age-related complications and may be eligible for treatment of that risk with alagebrium.

Background — CML Diagnostic

The process of aging naturally increases the presence of damaged proteins. Often this damage is caused by the attachment of glucose to proteins in a process called glycation. When the glucose–modified proteins go through further oxidation, the resulting modified protein is described as an Advanced Glycation Product (A.G.E.). These damaged proteins are often dysfunctional, inflammatory and damaging to organs such as the heart, kidney and skin among others. Collagen (a protein normally found in connective and structural tissue) is an example of a protein that can be converted into an A.G.E. As a consequence of advanced glycation and oxidation, collagen fibers can cross link, which makes them less flexible. When formed in the heart and blood vessels (the cardiovascular system), cross linked collagen induces stiffness, a loss of adaptability and decreased reactivity which makes the heart and blood vessels act less effectively and may increase the risk of cardiovascular complications.

It should not be surprising, that a disease like diabetes which is characterized by higher levels of circulating blood glucose can induce more A.G.E. formation and its associated complications.

A.G.E.s have no known salutary purpose and are often viewed simply as byproducts of living. They are scavenged by specialized receptors (RAGE, or receptors for A.G.E.s) on the surface of many cells. RAGEs not only internalize these waste products, but they trigger an inflammatory response in the cell. The RAGE-activated cell is induced to secrete factors that trigger the production of more collagen and elastin and other “fresh” connective tissue. Yet, the secretion of those factors (cytokines) has two undesired effects. First, cytokines may also cause leakiness in neighboring tissue. Second, they might promote the deposition of more connective tissue than is otherwise warranted in a location causing dysfunction.

CML, one highly common A.G.E. is believed to play a role in cardiovascular mortality, renal insufficiency, increased aortic stiffness, and other clinical phenomenon associated with aging. Synvista Therapeutics is conducting clinical trials to better understand the role of CML in age-related system decline.

Application

Preliminary studies are revealing that CML (and indeed the overall role of the A.G.E. and RAGE pathway) is relevant to the cause of loss in functionality of certain bodily systems (mainly the cardiovascular and renal systems). It seems clear that the presence and level of circulating CML and RAGE may be considered a biomarker for the likelihood of system decline. This is because CML in the blood is similar to serum cholesterol biomarkers in that they can be lowered by modifying diet or through drug intervention (e.g., use of statins). Synvista's current research is designed to clarify the relationship between A.G.E.s and RAGE with chronic cardiovascular and renal disease.

Once this relationship is understood, the company will develop a diagnostic test similar to its current haptoglobin technology to determine whether the CML biomarker is present and to follow its level in blood to better determine the utility of medications, such as alagebrium, an A.G.E. crosslink breaker, being evaluated in Phase II clinical trials by Synvista.