Asthma is disease manifested by chronic inflammation exacerbated by environmental insults such as allergens, infectious agents and irritants and affects 5-10% of the population. Interleukin 13 (IL-13) signaling is amplified in asthma and plays a central role in the pathogenesis of the disease. Our preliminary data strongly implicate the novel role of surfactant protein A (SP-A) in regulating IL-13 signaling in asthma. The mature SP-A protein is a large hetero-oligomer encoded by SP-A1 and SP-A2 genes. We have shown that SP-A isolated from asthmatic subjects is defective in abrogating inflammatory responses in human airway epithelial cells. This SP-A dysfunction could arise from genetic variation within the SP-A repertoire. Our preliminary studies demonstrate that a synthesized 10-mer SP-A2 223Q peptide, derived from one major allele of SP-A2, has activity similar to the full-length oligomeric SP-A in attenuating the biological responses to IL-13 in primary human epithelial cells and in mouse models of allergic airways disease. Taken together, these preliminary data led us to propose the novel hypothesis that a specific 10 AA sequence within the carbohydrate recognition domain (CRD) of SP-A confers the ability to significantly suppresses allergic inflammation. In our two specific aims, we will determine optimal formulations and dosing schedules for inhaled delivery of SP-A peptides to achieve therapeutic effects in mouse models of allergic airways disease. We will utilize FDA-approved human inhaler devices, FDA-approved excipients to deliver this novel SP-A peptide formulation in vivo via inhalation. Experiments will be conducted under FDA/USP conditions using required in vitro tests specified by the FDA/USP. In addition, in vitro 2D cell culture (i.e. liquid-covered culture and air-interface culture mimicking the air-liquid lung interface), in vitro 3D cell culture (i.e. air-interface culture), and in vivo pharmacokinetics/pharmacodynamics studies will be conducted. These studies will evaluate mechanisms influencing cell viability as a function of drug dose, particle-cellular membrane interactions, particle cellular uptake, membrane permeability, and drug cellular transport. SPA peptides and lung surfactant interactions will be examined with interfacial film studies. Finally, we will evaluate the efficacy of this novel SP-A peptide formulation and delivery method in a house dust mite model of allergic airways disease in mice. If successful, the proposed preclinical development studies would lay the foundation for subsequent clinical trials for patients with asthma.

Public Health Relevance

Asthma is a chronic disease of the airways characterized by inflammation and obstruction and affects approximately 10% of the US population. This proposal will evaluate an innovative treatment for asthma that involves a 10-amino acid peptide sequence that is derived from the active site of an endogenous lung protein, surfactant protein-A, using human lung cell lines and mouse models. Our preliminary data suggest that this peptide attenuates phenotypes associated with asthma, including inflammatory cell recruitment, mucin production and airway hyper-responsiveness. Optimization of the SP-A peptide may yield a new class of therapy for asthma sufferers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI135935-02
Application #
9607994
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Minnicozzi, Michael
Project Start
2017-12-05
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arizona
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Dy, Alane Blythe C; Tanyaratsrisakul, Sasipa; Voelker, Dennis R et al. (2018) The Emerging Roles of Surfactant Protein-A in Asthma. J Clin Cell Immunol 9: