Drug repurposing to treat asthma and allergic disorders: Progress and prospects.

Allergy and atopic asthma have continued to become more prevalent in modern society despite the advent of new treatments, representing a major global health problem. Common medications such as antihistamines and steroids can have undesirable long-term side-effects and lack efficacy in some resistant patients. Biologic medications are increasingly given to treatment-resistant patients, but they can represent high costs, complex dosing and management, and are not widely available around the world. The field needs new, cheap, and convenient treatment options in order to bring better symptom relief to patients. Beyond continued research and development of new drugs, a focus on drug repurposing could alleviate this problem by repositioning effective and safe small-molecule drugs from other fields of medicine and applying them toward the treatment for asthma and allergy. Herein, preclinical models, case reports, and clinical trials of drug repurposing efficacy in allergic disease are reviewed. Novel drugs are also proposed for repositioning based on their mechanism of action to treat asthma and allergy. Overall, drug repurposing could become increasingly important as a way of advancing allergy and atopic asthma therapy, filling a need in treatment of patients today.

Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors.

BACKGROUND: The formation of neutralizing antibodies (inhibitors) directed against human coagulation factor VIII (hFVIII) is a life-threatening pathogenic response that occurs in 20-30% of severe congenital hemophilia A patients and 0.00015% of the remaining population (i.e. acquired hemophilia A). Interspecies amino acid sequence disparity among FVIII orthologs represents a promising strategy to mask FVIII from existing inhibitors while retaining procoagulant function. Evidence for the effectiveness of this approach exists in clinical data obtained for porcine FVIII (pFVIII) products, which have demonstrated efficacy in the setting of congenital and acquired hemophilia. OBJECTIVES: In the current study, recombinant (r) ovine FVIII (oFVIII) was evaluated for antigenicity and procoagulant activity in the context of human patient-derived and murine model-generated FVIII inhibitors. METHODS: The antigenicity of roFVIII was assessed using (i) inhibitor patient plasma samples, (ii) murine anti-FVIII MAbs, (iii) immunized murine hemophilia A plasmas and (iv) an in vivo model of acquired hemophilia A. RESULTS: Overall, roFVIII demonstrated reduced reactivity to, and inhibition by, anti-hFVIII immunoglobulin in patient plasmas. Additionally, several hFVIII epitopes were predicted and empirically shown not to exist within roFVIII. In a murine hemophilia A model designed to mimic clinical inhibitor formation, it was demonstrated that inhibitor titers to roFVIII were significantly reduced when compared with the orthologous immunogens, rhFVIII or rpFVIII. Furthermore, in a murine model of acquired hemophilia A, roFVIII administration conferred protection from bleeding following tail transection. CONCLUSION: These data support the investigation of FVIII orthologs as treatment modalities in both the congenital and acquired FVIII inhibitor settings.