An Epigenetic Analysis of the ALOX5 Gene Related to the Clinical Response to Montelukast

An Epigenetic Analysis of the ALOX5 Gene Related to the Clinical Response to Montelukast

None.

None that would impact this research. The work concerns an off-patent drug (Merck)and no data related to any GSK product. I do own stock in GSK.

Montelukast is a drug used to treat asthma. However the improvement in asthma symptoms with Montelukast varies greatly between individuals. Work published by myself and others demonstrated that mutations in the gene (ALOX5) related to how Montelukast works, did have an effect on how well subjects with asthma responded to Montelukast, but was not predictive by itself to be a valuable test of who would respond and who would not. In order for Montelukast to be effective, the ALOX5 gene must be fully functional. The mutations in the gene we identified did affect the function of the gene, but not in all people. Therefore additional factors that affect the gene must exist. If the factors that affect response to Montelukast could be identified, then a simple test could be developed that would predict with accuracy who would be a good candidate to receive the drug for treatment of asthma symptoms. This would benefit asthma patients by knowing if the drug would work, thereby saving the expense and potential of putting the asthma patient at risk of complications because the drug is ineffective.

In addition to gene mutations that affect how the gene works, new genetic discoveries have found that presence of specific groups attached to DNA (methyl groups) can also affect the function of the gene. This process is called epigenetics, and has been proven to affect genes in certain diseases. The presence of these chemical groups on the DNA occurs at specific sites and can be easily measured. DNA was isolated from blood cells that were obtained from each patient that gave permission to do these tests, and participated in a clinical trial where response to Montelukast was measured. Groups on the DNA were measured by two different technologies in duplicate to assure accuracy. The ALOX5 gene contains many of these sites and thus response to Montelukast may be affected by the presence of these groups in the ALOX5 gene.

We selected patients that had a very good response to Montelukast and those that did not respond well to the drug to see if the ALOX5 DNA has these chemical groups. Statistical models will determine if the presence of these groups affect the response to Montelukast. A person's age, gender and ethnicity may also affect the presence of these groups attached to the DNA and these will be evaluated. We will look at each site on the ALOX5 DNA individually as well as groups of sites together to determine if the presence or absence of these groups can predict a person's response to the drug. Because the number of patients in this analysis is relatively small the results from this study would need to be repeated in a larger group of patients to determine its potential to predict who will respond to this drug. It is our intention to publish the results of this study so that other researchers can duplicate the findings in their patients.

[{ "PostingID": 1278, "Title": "GSK-SAS40020", "Description": "A Randomized, Double-Blind, Double-Dummy, Parallel Group, 12-Week Comparative Trial of Salmeterol/Fluticasone Propionate Combination Product 50/100mcg BID Via the DISKUS® Inhaler Versus Oral Montelukast 10mg QD in Adolescents and Adults with Persistent Asthma

Medicine: fluticasone propionate/salmeterol, Condition: Asthma, Phase: 4, Clinical Study ID: SAS40020, Sponsor: GSK" }]

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