Stroke (or "brain attack") is the third-leading cause of death in western countries. It's led only by ischemic heart disease and cancer. More than 600,000 individuals suffer a stroke each year in the U.S. Acute neurologic deficits resulting from circulatory impairment that resolve within 24 hours are downgraded as transient ischemic attacks (TIA). Most of these last only 15 to 20 minutes.

In contrast, a stroke involves irreversible brain damage. Its outcome varies from minimal impairment to rapid onset of coma followed quickly by death. The long rap sheet of risk factors that threaten stroke include: hypertension (high blood pressure), diseased heart valves, atrial fibrillation (palpitations), hyperlipidemia ("bad" cholesterol), diabetes mellitus, periodontal disease, chronic bronchitis, cigarette smoking and a family history of stroke.

Icelandic researchers report identifying a gene that is associated with susceptibility to stroke. Their findings appear in the current issue of Nature Genetics, released online Sept. 22, 2003, and scheduled for publication in October. Their article is titled "The gene encoding phosphodiesterase 4D [PDE4D] confers risk of ischemic stroke." Its co-senior author is medical geneticist and neurologist Kari Stefansson, chairman, CEO and president of the company DeCode Genetics Inc. of Reykjavik, Iceland. (See BioWorld Today, June 11, 2002.)

"The basic findings in this paper," Stefansson said, "are two in number. One is a gene that contains variants predisposed to the common form of stroke. The second, that we have a protein made by this gene, which in this instance is a good drug target.

"In collaboration with [F. Hoffmann-La Roche Ltd.] in Basel, Switzerland," Stefansson continued, "we started a drug discovery program on the basis of these molecules. We have gone to high-throughput screening and are very optimistic that it's going to lead us in the end, years down the road, to a drug that will prevent the genetic predisposition from being turned into stroke.

"The other category of implications," he went on, "allows us to identify the individuals who have a particular predisposition to the development of stroke. And why is that important? Because it can help to focus and contain stroke risks like hypertension. And they would also be the target population for the drugs designed against this particular protein. So these are the two industrial implications: the possibilities of facilitating drug development and of developing diagnoses. It is the first gene isolated in a disease of this complexity."

The article's lead author, geneticist Solveig Gretarsdottir, and her co-authors at DeCode last year mapped that PDE4D stroke-susceptibility gene to the long arm of human chromosome 5. To construct their high-resolution map, DeCode geneticists tapped 869 volunteers of Iceland's 277,906 total population. In the present study, working with doctors and researchers at Iceland's National University and its Heart Association, they report a large-scale screening to identify the gene in question, involving sampling 1,800 Icelandic adults who had suffered a stroke - both patients and unaffected relatives - from across Iceland.

Variant Levels Identify Changes In At-Risk Stroke

"Within this PDE4D gene," Stefansson observed, "our DeCode team identified haplotypes [specific sets of genetic markers] that correspond to both increased risk of stroke and significantly decreased risk. Expression and functional analyses of the gene strongly suggest that PDE4D plays an important role in atherosclerosis. This most likely is by influencing the proliferation and migration of smooth muscle cells within arteries, which is central to the biology of ischemic stroke.

"A drug that could inhibit PDE4D or one of its specific isoforms (variants) might therefore be useful in counteracting atherosclerosis, and thereby reduce the risk of stroke," Stefansson allowed. "DeCode and Hoffmann-La Roche, our commercial partner in the project, have initiated medicinal chemistry work on compounds we have identified as active against targets in the PDE4D pathway. Separately, DeCode is also developing a DNA-based diagnostic test based upon the at-risk and protective haplotypes within the PDE4D gene."

Although there are no variants in the gene itself connected to stroke, the authors did show that three different isoforms (variants) of the gene were expressed at lower levels in patients affected by the disease.

The PDE4D gene encodes the phosphodiesterase enzyme, which cleaves cyclic AMP. That molecule has numerous biological roles. As defined in animal studies, one such role is in the proliferation and migration of vascular cells. That may be involved in promoting atherosclerosis, a key risk factor for stroke. The co-authors suggest that designing small-molecule drugs targeting that gene in the at-risk population might prove to be beneficial. Phosphodiesterase inhibitors are already in use in other countries to treat asthma, inflammation and erectile dysfunction.

"Stroke is among the diseases that has highest incidence in old age," Stefansson commented, "and therefore it's becoming more and more common a disease in our society, probably the most common cause of disability.

"Environmental factors contribute to stroke," Stefansson noted. "It happens at the intersection between genes and environment. Any increase in blood pressure increases probability of stroke. Certain drugs of abuse increase that probability - for example, cocaine. One of the commonest risk factors occurs in very young people, who rarely develop stroke. The few instances when they do often follow heavy consumption of alcohol.

"Clearly, if you look at the role of genetics," he pointed out, "the beauty of isolating the genes is that when you have the equation between two unknowns, one is the genetic component, the other environmental. When you have found number one, it is simpler to find number two."

Drug Discovery Phase Now To the Forefront

"In furtherance of our ongoing research," Stefansson recounted, "we are now in a drug discovery phase, using the protein made by the gene as a target. We are also into the development of diagnostic tests based on genes. That is where we are putting most of our efforts these days.

"Of course we and Roche are jointly applying for patents to protect our investment for stroke medications. The big message now for biotechies is that we have technology that allows up to pull out genes in the common diseases. But also," he concluded, "because it gives us a new insight into the possible ways of treating and diagnosing diseases, and even preventing them."

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