Assay Objectives

Synvista is developing a diagnostic assay for haptoglobin that it believes can be used to: 1. determine which patients with diabetes should take vitamin E chronically to reduce their cardiovascular diseases risk, 2. identify which patients with diabetes are at high risk for cardiovascular complications.

Background — Haptoglobin Diagnostic

It is well known that patients with diabetes are at 2-4 times the risk of non-diabetics to develop cardiovascular disease (CVD) and ultimately 75 percent of diabetics die as a result of CVD-related illnesses. The role of oxygen free radicals and reactive oxygen species (ROS) in mediating the development of arteriosclerosis through the oxidative modification by ROS of the low-density-lipoprotein molecule (LDL) is thought to be the most prominent culprit in the onset of CVD. However, the CVD risks are not the same for all diabetics. Numerous studies have demonstrated the risk of developing more severe CVD is a function of a normal occurring serum protein called haptoglobin (Hp), which is an abundant plasma glycoprotein produced in the liver.

Haptoglobin’s best understood function is to bind free hemoglobin released from red blood cells. While most are familiar with the function of hemoglobin within blood cells to carry oxygen throughout the body, extracellular hemoglobin (hemoglobin not found in red blood cells) is a potent oxidizing agent capable of inflicting oxidative tissue damage. Haptoglobin binds to this extracellular hemoglobin and serves to inhibit the oxidative potential of hemoglobin by preventing the release of heme iron. Once hemoglobin is bound to haptoglobin, it is rapidly cleared from the bloodstream by either liver hepatocytes or the monocyte.

Haptoglobin in humans exists as 3 different proteins which arise from two alleles referred to as 1 and 2. In most Western populations the prevalence of the homozygote Hp 1-1 is about 16 percent, with 36 percent prevalence for homozygote Hp 2-2 and 48 percent for the heterozygote, Hp 2-1. The three different forms of haptoglobin prevent hemoglobin-induced oxidation at different rates with the Hp 1-1 the most potent anti-oxidant and Hp 2-2 the poorest. In vitro and in vivo studies have demonstrated the Hp genotype and diabetes dependent differences in oxidative stress and in the generation of cellular stress. It appears that the diabetic hyperglycemic milieu is critical for the manifestation of the different haptoglobin genotypes in determining the risk of CVD.

As a result, scientists have determined that there is a fivefold increase in Hp 2-2 diabetic individuals of having incident heart disease. There is a two-threefold increase in risk for diabetic Hp 2-2 individuals to sustain a myocardial infarction or re-vascularization within 1 year of PCI. Finally, there is an increased rate of heart failure and a sevenfold increased rate of death for Hp 2-2 diabetic individuals within 30 days of a heart attack. Several longitudinal studies have demonstrated these various risks of incident CVD and its relationship to haptoglobin genotype (click here for links to some of these studies).

Currently, Synvista is developing a proprietary diagnostic test to determine haptoglobin genotype in order to identify the subset of diabetics at greatest risk for CVD. Since this test determines which diabetic patients display the highest levels of oxidative stress (Hp 2-2 individuals) it can also be used to identify the subset of diabetics who will benefit most from potent anti-oxidizing agents.

The test is being developed to be used on current ubiquitous laboratory platforms (e.g., ELISA), and also to be used in genetic testing labs. The test is also being developed such that it applies to CMS parameters for reimbursement. Once available, the Company plans to distribute the test to hospitals and other independent labs that have high volume customers.

To bring the most effective therapy to patients who will benefit most, Synvista has developed an extensive intellectual property portfolio based on utilizing haptoglobin genotyping to target the use of anti-oxidizing agents on a specific population of diabetic individuals with the Hp 2-2 genotype, thereby creating an unique product portfolio that both identifies a specific patient profile and provides therapeutic solutions to address the needs for these patients.