ChemGenex pinpoints inflammation gene

Diabetes- and oncology-gene hunter ChemGenex Pharmaceuticals (ASX:CXS) now has solid evidence that a particular variant of the SEPS-1 gene, already identified as a trigger for Type 2 diabetes, is a strong risk factor for a broad range of chronic inflammatory disorders.

ChemGenex researchers identified the chromosome 15 gene - originally called TANIS - five years ago while searching the genome for diabetes susceptibility genes.

In an on-line Nature Genetics research paper published this week, an Australian-US research team describes how the polymorphism contributes to inflammatory processes. ChemGenex CEO Greg Coliier said today that a preliminary estimate suggests around 25 per cent of Westerners carry a pro-inflammmatory variant of the selenium protein S-1 (SEPS-1) gene -- one in four people are at increased risk of a spectrum of inflammatory disorders including diabetes, cancer, obesity and cardiovascular disease -- the only upside is that a heightened inflammatory response may allow them to respond more effectively to infection.

Given that the SEPS-1 gene's basic role in inflammation, ChemGenix owns the IP to an exciting new target for anti-inflammatory drugs, as well as for a prognostic gene test for susceptibility to type 2 diabetes and other inflammatory disorders including, cancer, obesity, and cardiovascular disease.

The SEPS-1 gene normally restrains the inflammatory process by limiting production of inflammatory cytokines when cells come under stress - including oxidative and metabolic stress, such as elevated glucose concentrations in diabetics.

Collier said a simple GA mutation in the gene's promoter reduces the gene's expression, in turn resulting in over-expression of inflammatory cytokines like interleukin-6 and TNF-alpha - the latter is the target for blockbuster anti-inflammatory therapies like Centacor's Remicade and Abbot's Humira.

Collier said the SEPS-1 gene is now identified as a promising target for drugs that would suppress inflammation by up-regulate its expression to normal levels.

The gene normally has a critical role in eliminating misfolded proteins in the endoplasmic reticulum, by helping 'label' aberrant proteins, including oxidation-damaged molecules. The inefficient allele allows abnormal and oxidized proteins to accumulate in the cell, triggering the release of inflammatory cytokines.

"If someone carries that gene variant, they will have an elevated inflammatory response, and a chronic background of increased inflammatory response," Collier said.

He said the high prevalence of the pro-inflammatory variant of the gene in the population was a probably the evolutionary legacy of a time when early humans were frequently exposed to infectious disease; in such circumstances, the variant was protective. Today, with people living longer, the consequence was an increased susceptibility to inflammatory diseases as people age.

"The immediate application, on the diagnostic front, is that we can look at lifestyle interventions for people in the high-risk subgroup," Collier said. "That opens up opportunites in the field of personalized medicine, which is the space in which ChemGenex wants to position itself commercially.

"We think personalized medicine is the future - Vioxx [the Merck COX-2 inhibitor alangesic recently withdrawn from sale] would still be on the market if today if the company had been able to sub-group those responders in whom it causes cardiovascular disease and stroke."