title: Barriers to inhaled gene therapy of obstructive lung diseases: A review.
abstract: Knowledge of genetic origins of obstructive lung diseases has made inhaled gene therapy an attractive alternative to the current standards of care that are limited to managing disease symptoms. Initial lung gene therapy clinical trials occurred in the early 1990s following the discovery of the genetic defect responsible for cystic fibrosis (CF), a monogenic disorder. However, despite over two decades of intensive effort, gene therapy has yet to help patients with CF or any other obstructive lung disease. The slow progress is due in part to poor understanding of the biological barriers to inhaled gene therapy. Encouragingly, clinical trials have shown that inhaled gene therapy with various viral vectors and non-viral gene vectors is well tolerated by patients, and continued research has provided valuable lessons and resources that may lead to future success of this therapeutic strategy. In this review, we first introduce representative obstructive lung diseases and examine limitations of currently available therapeutic options. We then review key components for successful execution of inhaled gene therapy, including gene delivery systems, primary physiological barriers and strategies to overcome them, and advances in preclinical disease models with which the most promising systems may be identified for human clinical trials.
authors.affiliation: The Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Namho
authors.initials: N
authors.lastname: Kim
authors.affiliation: The Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Duncan
authors.affiliation: The Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Environmental and Health Sciences, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: The Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: jsuk@jhmi.edu.
authors.forename: Jung Soo
authors.initials: JS
authors.lastname: Suk
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000280:Administration, Inhalation; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008173:Lung Diseases, Obstructive / Q000235:genetics / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics
chemical_list: D004337:Drug Carriers
keywords: Biological barrier; Gene delivery vector; Preclinical model; Respiratory gene therapy