By David N. Leff

Whether for acne, arthritis, baldness, incontinence, impotence or whatever trendy ailment, TV commercials have just the drug. But whichever remedy they tout, they always throw in the disclaimer that "Drug X may not be for you. Consult your doctor."

When it comes to relieving asthmatic attacks, the front-running medicine by far is albuterol. It zeroes in on the constricted bronchial airways that leave asthma sufferers gasping for breath - and sometimes for life itself.

Some 17 million Americans suffer from asthma - 4.8 million of them children and youngsters under 18 years of age. And about 5 million die of the disease each year. So when an anxious parent consults the doctor, he or she consults the desk-reference pharmacopeia, which lists 27 brands of albuterol, a prescription bronchodilator taken by inhalation.

The bad news it that albuterol, for all its pharmaceutical primacy, works well in only a fraction of the asthma patients for whom it's prescribed. "It's been known for a long time," observed molecular geneticist Stephen Liggett, at the University of Cincinnati, "by those of us who take care of asthma, that certain individuals respond very well to asthma medications, and some do not. Except for the mildest cases, for the rest of the asthmatics there's always been a large bit of trial and error involved in trying to decide which of the different multiple types of medications that are available for treating asthma will be appropriate for a given individual. This has resulted in people being on too many medications, or suffering side effects from a given drug, which may not be necessary.

"And because asthma is one of those diseases," he continued, "that waxes and wanes with the seasons, and with upper respiratory infections, it's difficult when one starts a drug to know if it's having a significant impact or not. So there's a need in this disease for physicians to have an aid in knowing whether or not a person is genetically programmed to be responsive to a given medication."

Liggett addressed these remarks yesterday - Tuesday, Sept. 12, 2000 - to a national telephone conference conducted by himself and scientists at Genaissance Pharmaceuticals (GP), in New Haven, Conn. Its theme: "New asthma research opens the door to using organized genome markers to develop personalized medicines."

Industry, Academia In Crystal-Balling Drug Test

The conference presented findings reported in the current Proceedings of the National Academy of Sciences (PNAS), also dated Sept. 12, 2000. Liggett is senior author of the PNAS paper, titled, "Complex promoter and coding region b2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness." Its co-senior author is Gualberto Ruaqo, CEO of Genaissance.

"In this collaboration between our university lab and GP," Liggett explained to his phone-in listeners, "the basic concept we were exploring was to examine a very common disease, asthma, and one of the most commonly used drugs to treat asthma, albuterol."

The team's clinical "real world" trial tested 121 asthmatic volunteers recruited from patients who came to Liggett's clinic seeking relief from their symptoms. Their individual responses to albuterol were correlated to the DNA sequence variations found in the gene encoding the drug's target, the b2-adrenergic receptor. They found that gene to have 13 different sequence variations, or single nucleotide polymorphisms - SNPs. Theoretically, these 13 SNPs could be arranged into 213 - i.e, 8,192 - possible combinations of haplotype markers.

Ruaqo, GP's CEO, defined haplotypes: "Our proteins are made from a single chromosome in the cell biology of any given cell type. When you make a protein, it's made from a single locus in the chromosome, and usually it's a mixture of both chromosomes contributed [by both parents] to synthesizing it.

"So the bottom line," Ruaqo continued, "is that what we call protein is really the result of mutliple polymorphisms - mutant SNPs - that occur in that gene locus in that chromosome. Therefore the haplotye is in a real sense an isoform of the gene. And that isoform will be reflected in the sequence of the amino acids and on the expression level of messenger RNA that eventually makes the protein. Therefore, to reconstitute physiology, you need the whole locus of the chromosome, and that whole locus is the haplotype."

GP's Connie Drysdale, the PNAS paper's lead author, proffered a handier, dandier definition: "We were faced with a very difficult challenge in taking on this very challenging disease, asthma, and trying to extract something like a genetic bar code in our haplotype technology."

"The power of this haplotypic analysis," Liggett observed, "allowed us to look at 121 asthmatics, and make a very strong prediction as to who would respond to the albuterol. Results were representative of what a doctor would see in general practice."

"There was a range of responders," Ruaqo summed up. "The best ones, catalogued by haplotype, were roughly 7 percent - super-responders. The next category was 21 percent, so a quarter of the best responders can be selected or predicted on the basis of the haplotype markers. The extremely poor responders were about 12 percent. So those children should be put on alternative therapy, rather than waste time with albuterol medication."

Other Disease Medications On Drawing Board

Asthma is only the first disease in GP's pipeline. Others include diabetes, arrhythmias and schizophrenia. And besides predicting responses to medicines on the market, the company's program includes testing new drugs under development.

"We feel," Liggett foresees, "that this is the first in a long line of haplotype markers that will be developed in these complex diseases. Ultimately, a person may come to the doctor's office with a new diagnosis of, let's say, asthma, and a genetic panel of haplotype markers can be obtained, which will give the physician a read-out of the probability of the patient responding to all of the commonly utilized drugs in the treatment of that disease.

"Of course, this is not going to replace physician judgment," he concluded, "but it's going to provide for what we call personalized medicine. And something we've known from the dawn of medicine, that different patients respond differently to different treatments, can be placed into a more objective framework, and will provide for what we believe to be a marked enhancement in patient care."

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