Effective treatment of experimental ragweed-induced asthma with STAT-6-IP, a topically delivered cell-penetrating peptide.

BACKGROUND: Treatment of allergic airways disease including asthma remains primarily local immunosuppression with topical corticosteroid and symptomatic management with antihistamines and anti-leucotrienes. We have developed a novel topical therapy designed to specifically inhibit the events associated with Th2 cell activation.

OBJECTIVE: We assessed the efficacy of our cell-penetrating STAT-6 inhibitory peptide (STAT-6-IP), a novel treatment for allergic airways disease, in a model of chronic ragweed-induced asthma.

METHODS: Six- to eight-week-old mice were sensitized over 5 weeks with intranasal (IN) exposures to whole ragweed allergen without adjuvant. Mice were then IN challenged with Amba 1 with and without treatment IN with STAT-6-IP and allergic responses assessed. Two weeks later, some animals were rechallenged with Amba 1 with or without STAT-6-IP.

RESULTS: Animals exposed to IN ragweed developed significant airway hyperresponsiveness and airways inflammation upon challenge. Cell cultures showed increases in Th2 cytokines IL-4 and IL-13. Topical STAT-6-IP treatment reduced production of Th2 cytokines, demonstrated increased expression of IL-10 and reduced frequency of cultured IL-4 positive CD4+ T cells derived from treated mice, suggesting that STAT-6-IP treatment may be immunomodulatory. Airway responsiveness to methacholine challenge in the treatment group was similarly reduced to that of the non-allergic PBS-exposed animals. Importantly, STAT-6-IP-treated mice remained hyporesponsive following second ragweed challenge 2 weeks after treatment.

CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that topical application of the STAT-6-IP is sufficient to inhibit allergic airways responses in animals chronically sensitized and challenged with ragweed. Data show that a single topical treatment course is sufficient to block signs of allergic responses to ragweed in the airways for at least 2 weeks. STAT-6-IP is a novel potential treatment for chronic allergic asthma.