Wednesday, September 13, 2000

Genetic bar code study promising

Technology could focus treatment

By Tim Bonfield
The Cincinnati Enquirer

        Imagine a day when doctors can use a patient's genetic profile to predict with near certainty whether a medication will treat their illness or cause a dangerous side effect.

        That day has become much closer with the publication Tuesday of a genetic study of people with asthma, led by University of Cincinnati researcher Dr. Stephen Liggett and co-sponsored by Connecticut-based biotech company.

  • SNPs: Single nucleotide polymorphisms. A single point of variation within a gene that can influence susceptibility to a disease or response to a medication. A gene can have many SNPs
  • HAPs: Haplotypes. Each haplotype reflects one of the many possible combinations of SNPs that can be found on a gene.
  • Human Genome Project: A nearly complete effort to map the entire sequence of 3.1 billion subunits of DNA that spell out the human genetic code.
  • Asthma: A disease suffered by an estimated 17 million Americans in which the bronchial airway contracts to cause wheezing and difficulty breathing.
  • Albuterol: The most commonly used drug to control acute asthma attacks.
  • A genetic test for asthma patients using albuterol could be commercially available within a year, pending regulatory approval.
  • Researchers hope to expand the technology to other diseases, such as diabetes and schizophrenia.
  • Eventually, genetic screening technology may breathe new life into once-promising medications that have been pulled off the market over concerns about side effects.
        The study, published in the Proceedings of the National Academy of Sciences, analyzed 121 Tristate asthma patients to predict who would respond to albuterol, the most commonly prescribed asthma drug. To do this, researchers organized genetic information in a way they say is like developing a bar code for people.

        “We know from experience that some individuals just do not respond very well to some medications, yet others have wonderful responses,” Dr. Liggett said. With this kind of genetic test “we can shorten that trial- and-error period, which would improve care and save costs.”

        Overall, the study advances the concept of “personalized medicine,” in which doctors hope to use genetic information to customize an individual's diagnosis and treatment rather than rely on a process of trial and error. By proving the technology works, the study raises several implications:

        • A genetic test for asth

        ma patients could be commercially available within a year. An estimated 17 million Americans have asthma, and about 5,000 die from it every year.

        • Researchers plan to expand the technology to other diseases, such as diabetes, schizophrenia and heart conditions.

        • Eventually, genetic screening technology may breathe new life into once-promising medications that had been pulled off the market over concerns about side effects.

        The gene-analyzing technology was developed by Genaissance Pharmaceuticals, a New Haven, Conn.-based company formed in 1997 by researchers affiliated with Yale University.

“We believe this is a landmark event,” said Dr. Gualberto Ruano, chief executive of Genaissance. “We intend to replicate this kind of analysis in many other diseases.”

        With the near completion of the Human Genome Project, new understanding about the basic blueprint of the human body has prompted an explosion of biotech research. Among the recent trends has been a focus on single nucleotide polymorphisms (SNPs).

        Dr. Liggett and other geneticists have been studying how these tiny variations within a single gene can influence whether a person is likely to develop a disease or how well they may respond to medications.

        However, an SNP is like a single line in a bar code; its information and predictive power is limited, Dr. Liggett said. For the asthma study, Genaissance developed entire bar codes, called haplotypes (HAPs), based on combinations of 13 SNPs found on a gene known to influence the disease.

        Dr. Liggett said certain HAPs showed strong correlations with how patients responded to medication, but no single SNP had a powerful predictive effect.

        In the study, about 12 percent of patients had a type of HAP that made them unresponsive to albuterol. That means a doctor armed with such information could start an asthmatic on any of a dozen other drugs.

        “This is a significant observation,” said Dr. William Busse, an asthma expert at the University of Wisconsin. “If we could find a gene variable that would enable a doctor to make predictions about how people would respond to a medicine, it would be very useful.”

        Accurate genetic screening also could influence drug development. For example, the diabetic drug Rezulin was pulled from the market after some patients wound up with liver problems.

        The once-popular weight-loss drug fen-phen suffered a similar fate when some people suffered heart valve damage.

        If dangerous side effects of Rezulin or other drugs can be shown to be limited to people with specific types of HAPs, then patients without those HAPs could safely benefit from the medication, Dr. Liggett said.

       The Associated Press contributed to this report.

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