Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States; there is no curative treatment. Both genetic and biomarker surveys strongly implicate dysregulated TGF-? signaling as a contributor to COPD development and progression. Excessive TGF-? signaling results in airway obstruction caused by epithelial thickening and alveolar epithelial cell apoptosis with airspace simplification, each of which is observed in mouse models and patients with COPD. We recently showed that TGF-? antagonism with systemic angiotensin receptor blockers (ARB) protected against pulmonary damage in mice exposed to chronic cigarette smoke (CS) and reversed airspace enlargement in a transgenic mouse model of emphysema. ARB administered orally provides very little drug delivery to the lungs and also cause significant systemic side effects. Thus, we have focused on the development of ARB formulations that could be delivered directly to the lung via inhalation by nebulization. Our pilot data suggests that local administration of an ARB compound, formulated in a novel ?mucus-penetrating particle nanocrystal? (MPP-NC) for inhalation, provides significantly enhanced lung drug levels (compared to a conventional oral formulation) and effective TGF-? antagonism, resulting in protection against TGF-?-mediated lung injury. Of note, the ARB MPP-NC formulations are composed entirely of materials that are generally regarded as safe, thereby making our approach potentially highly translational. We also introduce an elegantly simple approach to maximize lung distribution and retention of inhaled therapeutics, namely hypo-osmolar vehicle solutions. We plan to develop MPP-NC formulations with eight potent FDA-approved ARB drugs and thoroughly characterize in vitro, followed by screening of promising formulations for TGF-? antagonism in an acute CS-exposed mouse model of lung injury. The most promising formulations delivered in an optimized hypo-osmolar vehicle solution will be tested for pharmacokinetics, safety, and therapeutic efficacy following repeated local administration in a chronic CS-exposed mouse model of COPD.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in United States, yet there is no cure or therapy that alters the natural history of the disease. We and others have found that a particular cytokine, called TGF-?, contributes to COPD onset and progression. We propose to repurpose a class of drugs, angiotensin receptor blockers, that we have shown target the underlying disturbances in TGF-? signaling in lung disease, into novel nanotechnology-based drug formulations that can be inhaled in an optimized vehicle solution to better treat COPD while minimizing unwanted drug-related side-effects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL136617-04
Application #
9948731
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Punturieri, Antonello
Project Start
2017-06-01
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Duncan, Gregg A; Kim, Namho; Colon-Cortes, Yanerys et al. (2018) An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy. Mol Ther Methods Clin Dev 9:296-304
Huang, Xinglu; Chisholm, Jane; Zhuang, Jie et al. (2017) Protein nanocages that penetrate airway mucus and tumor tissue. Proc Natl Acad Sci U S A 114:E6595-E6602
Schneider, Craig S; Xu, Qingguo; Boylan, Nicholas J et al. (2017) Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation. Sci Adv 3:e1601556