A collaborative model for drug development for rare diseases

This month’s issue holds an article by Fiorentino et al. putting forward a model for rare disease drug development and the first realization of this model (J Allergy Clin Immunol 2012;130:613-616). Fiorentino and colleagues at the FDA in CDER’s Division of Gastroenterology and Inborn Error Products chose the rare disease eosinophilic esophagitis (EoE) as the focus of their efforts to establish this new paradigm.

Noting the rise in prevalence and incidence of EoE, the authors discuss the knowledge gaps that create obstacles to effective clinical interventions. They use this information to construct their model of “rational” drug development, which includes defining the disease in clinical, research and sociocultural terms, evaluating the natural history of the disease using the definitions identified, and reliably assessing clinical and patient-reported outcomes.

Fiorentino et al. describe their efforts to date implementing this model. They tapped critical research groups, such as The International Gastrointestinal Eosinophil Researchers (TIGERs), North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) to open discussions on disease definition and urge the inclusion of disease and patient advocacy groups in this early process. Advocacy groups are identified as critical to the success of the model because they bring strong interest in the long-term success of research into the disease.

Early progress is reported for the determination of a functional disease definition and appropriate terminology. The authors note that findings from graduate student research supported by the EoE project demonstrate that inconsistent and vague terminology is impeding research efforts. Additionally, they comment that research is underway to understand the relationship between positive clinical outcomes and the esophageal mucosal eosinophilia that is diagnostic for EoE. They point out that there is a pressing need to define and characterize the EoE patient population in order to develop appropriate patient-reported outcome measures.

An editorial in this issue by Rothenberg et al. presents additional perspectives and considerations (pp#). Dr. Rothenberg notes that an upcoming meeting (Sept. 19) provides an opportunity for more information and exchange of opinion about the subject. For further information: https://www.signup4.net/public/ap.aspx?EID=20123759E&OID=50

A large cohort analysis of allergic outcomes from peanut and tree nut consumption during pregnancy

Current research has challenged the conventional wisdom of dietary avoidance of food allergens during pregnancy. A recent study from the UK found that avoidance of peanuts, specifically, during pregnancy did not confer significant protection from peanut allergy to the infant. Accordingly, the UK removed that recommendation. In the US, avoidance is only recommended for children at risk by heredity.

In this issue, Maslova et al. (J Allergy Clin Immunol 2012;130:724-732) from Center for Fetal Programming, Statens Serum Institut, present important results from an analysis of a very large Danish birth cohort (n=61,908). The authors look at development of asthma, wheeze, and allergic rhinitis – not food allergy – in children whose mothers consumed peanuts and tree nuts during pregnancy as compared to children whose mothers avoided these foods.

At 18 months, children whose mothers ate peanuts more than once a week were less likely to have parent-reported asthma, while children whose mothers ate tree nuts were less likely to report asthma, wheeze and recurrent wheeze. At 7 years, children of mothers who ate peanuts and/or tree nuts were less likely to have a registered diagnosis of asthma. These results all reached statistical significance. The association of tree nut consumption during pregnancy with decreased likelihood of self-reported allergic rhinitis during the first 7 years of life was borderline statistically significant.

Maslova et al conclude by suggesting that their results do not support avoidance or decreased consumption of peanuts and tree nuts during pregnancy. 

Secretory phenotype of mast cells localized in nasal polyps from chronic rhinosinusitis subjects

Takabayashi et al. present novel findings in this issue on the distribution and protease secretion of mast cells (MC) found in nasal polyps from subjects with chronic rhinosinusitis (CRSwNP) (J Allergy Clin Immunol 2012; 130:410-420.e5). The authors compared MC from the epithelium, glands, and submucosa of CRSwNP with uncinate biopsy tissue (UT) from subjects with CRS without nasal polyps (CRSsNP) and control subjects.

They found mast cells numbers were highly increased in NP epithelium and glands, in particular, as compared to UT from CRSsNP and control subjects. Further, the MC populations in NP were distinguishable on the basis of their protease profile. Mast cells from the NP epithelium were tryptase-carboxypeptidase A3 (CPA3)-positive/chymase-negative, while MC from NP glands were tryptase-CPA3-chymase-positive.


The authors note clear expansion in MC numbers that they suggest could be the result of increased migration and accumulation as well as proliferation. Since mast cell tryptase can activate protease-activated receptor (PAR) 2, which facilitates allergic inflammation, and mast cell chymase can activate PAR-1 signaling and is a potent glandular secretagogue, the results of Takabayashi et al suggest that mast cells localized in submucosal glands may be well positioned to drive important features of the inflammatory response associated with chronic rhinosinusitis and nasal polyp formation.