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For ChondroGene, Blood May Be Thicker Than Biopsy Tissue for Pharmacogenomic Research

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SANTORINI, Greece — Toronto-based ChondroGene will soon release a database that links gene expression found in blood cells with disease states, to be followed by biomarker diagnostic kits based on data generated using the approach.

The technology — which Choong-Chin Liew, ChondroGene co-founder and cheif scientist, and director of the Cardiovascular Genome Center at the Brigham and Women’s Hospital at Harvard Medical School, calls the “sentinel principle” — may enable researchers to detect disease and monitor drug response through blood cell gene expression analysis, Liew told attendees at the 3rd annual meeting of the International Society of Pharmacogenomics, held here last week.

Nucleated blood cells, rather than traditional biopsied tissue samples are the focus of Liew’s sentinel. Blood comes into contact with nearly all human tissues, and cellular crosstalk changes the gene expression patterns in blood’s component cells, patterns that researchers — and eventually clinicians — can read to assess disease and drug response, said Liew.

“In coronary artery disease, in blood extractions from patients undergoing angioplasty, you can really see a different gene expression in whole blood RNA samples,” Liew said during the meeting. “The hematopoietic system becomes a mirror that reflects what is going on. You look at the mirror to see the phenotype. It is in between basic information and dynamic information. So, you have to come up with a technology that lets you detect this,” Liew said.

In his lecture, Liew concentrated on his laboratory’s use of microarray technology to profile gene expression in dilated cardiomyopathy, hypertrophic cardiomyopathy, and Chagas’ disease. With real-time RT-PCR, his lab revealed DCM and HCM to be “linked to dysregulation in force transmission pathways,” said Liew.

He classified DCM as a “cytoskeletalopathy” and HCM as a “sarcomyopathy.” Chagas’ disease, a heart condition that appears in people previously infected by a particular parasite, is a “cytokinopathy,” in which chronic exposure to cytokines results in myocardial damage and inflammation-induced gene expression, he said.

ChondroGene performs in-house gene expression studies with its human cartilage-specific ChondroChip cDNA microarray and Affymetrix’s whole-genome arrays to find biomarkers for “life-altering” diseases, said ChondroGene CEO K. Wayne Marshall.

But “soon” ChondroGene will launch “a very big database relating a large number of diseases” to gene expression based on sentinel principle data, said Liew. Slated for release in about a year — initially as a research-only product — is an osteoarthritis quantitative RT-PCR gene-expression kit the company is developing with Pfizer.

“If we decide to go through the [US Food and Drug Administration] it will take perhaps five years. We are in the process to go through the FDA,” said Liew. He declined to say when the company would file with the agency.

Additionally, the company is “processing” a human gene chip containing full cDNA probes of all 30,000 genes, said Liew. The chip was developed for in-house research at ChondroGene, with the advantage that full cDNA copies of a gene can be produced “immediately” after an important gene is identified, he added. “You can very quickly reproduce the protein, and you can use it very quickly, generate an antibody, et cetera,” said Liew.

Whether the chip will be launched as a product depends on the market, which is dominated by Affymetrix and Agilent, said Liew.

Marshall said the company was not yet ready to discuss any upcoming products, but he mentioned the company’s Oct. 27 presentation at the Rodman and Renshaw Techvest 6th Annual Healthcare Conference.

Other projects are on the horizon involving collaborations with different pharmaceutical companies, said Liew. “Once we really get this type of technology working, it’s really important that we leap to clinical trials. If a pharma company wants to set up a Phase II, it might be the best way to isolate expressed genes related to drug action,” he said.

In his research of disease-related genes, Liew views “all cell interactions” by looking at the expression patterns of all 30,000 human genes, he said. Most of these clearly are not related to disease states, so he examines the blood of a “huge” number of patients to find out which are consistently “important,” Liew added.

Using this broad method, Liew and colleagues at ChondroGene are working with Pfizer to study biomarkers related to osteoarthritis, and they have discovered several T-cell specific genes correlated with the disease, said Liew. “We are the only companies doing this,” he said.

Even though joints are very well insulated from the circulatory system, the hematopoietic system can reflect disease stages very well, said Liew. In osteoarthritis, you determine the damage using X-rays or a biopsy sample, but the method he and colleagues have developed can detect damage earlier, he added.

With sensitive enough biomarkers, and early osteoarthritis detection, doctors will be able to prescribe anti-inflammatory drugs at lower doses, said Liew. “If you can detect any disease at an early stage, the cost of treatment will be much cheaper, and it is much, much easier to get the person to recover or to delay the onset of disease,” he said.

The ultimate goal is to find genes most important to a disease, and in Phase II clinical trials, test those genes alongside drug response to see “whether they respond or how effective they are.”

— CW

 

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