Asthma is now thought to affect 155 million people worldwide. In the United States alone there has been a two-fold increase in the number of cases of asthma and consequently the market is large standing at $8 billion worldwide. Despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, increasing the demand for novel therapies that possess new modes of action. The role of specific chemokine receptors during allergic asthmatic responses has been relatively undefined. A number of receptors are preferentially expressed on Th2 cells, including CCR4, CCR8, and CxCR4. At least 7 CxCR4 receptor antagonists have been developed, however this has generally been for the treatment of HIV-1 infection and/or cancer, and, to date, little attention has been paid to asthma. AnorMED's AMD-3100 was one such CxCR4 receptor antagonist in development for HIV-1, however it did not meet the criteria for efficacy in its Phase Ib/IIa trial and caused abnormal cardiac activity in 2 patients. Last year therefore, the company shifted its attention to the antiinflammatory activity of this molecule. Currently indicated for the treatment of rheumatoid arthritis, the role of the CxCR4 receptor and the therapeutic potential of antagonists of this receptor such AMD-3100 in airway disease has now been investigated. Thus, University of Michigan researchers have recently reported that AMD3100 significantly down-regulated the inflammation and pathophysiology of the allergen-induced response. Treatment of allergic mice with AMD3100 significantly reduced airway hyperreactivity, peribronchial eosinophilia, and the overall inflammatory responses. In addition, a shift in the cytokine profile was observed in AMD3100-treated animals. Specifically, there was a significant reduction in interleukin-4 and interleukin-5 levels and a significant increase in interleukin-12 and interferon-gamma levels within the lungs of treated allergic mice. Furthermore, there was a significant alteration in the local chemokine production of CCL22 (MDC) and CCL17 (TARC), two chemokines previously shown to be important in Th2-type allergen responses. Overall, specifically blocking CxCR4 using AMD3100 reduced a number of pathological parameters related to asthmatic-type inflammation suggesting that CxCR4 receptor antagonists including molecules from the AMD3100 series may play a role in treating airway inflammation.

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