Journal article
Dual therapeutic utility of proteasome modulating agents for pharmaco-gene therapy of the cystic fibrosis airway
Molecular therapy, Vol.10(6), pp.990-1002
2004
DOI: 10.1016/j.ymthe.2004.08.009
Abstract
Pharmacologic- and gene-based therapies have historically been developed as two independent therapeutic platforms for cystic fibrosis (CF) lung disease. Inhibition of the dysregulated epithelial Na channel (ENaC) is one pharmacologic approach to enhance airway clearance in CF. We investigated pharmacologic approaches to enhance CFTR gene delivery with recombinant adeno-associated virus (rAAV) and identified compounds that significantly improved viral transduction while simultaneously inhibiting ENaC activity through an unrelated mechanism. Treatment of human CF airway epithelia with proteasome modulating agents (LLnL and doxorubicin) at the time of rAAV2 or rAAV2/5 infection dramatically enhanced CFTR gene delivery and correction of CFTR-mediated short-circuit currents. Surprisingly, these agents also facilitated long-term (15-day) functional inhibition of ENaC currents independent of CFTR vector administration. Inhibition of ENaC activity was predominantly attributed to a doxorubicin-dependent decrease in gamma-ENaC subunit mRNA expression and an increase in gamma-ENaC promoter methylation. This is the first report to describe the identification of compounds with dual therapeutic action that are able to enhance the efficacy of CFTR gene therapy to the airway while simultaneously ameliorating primary aspects of CF disease pathophysiology. The identification of such compounds mark a new area for drug development, not only for CF, but also for other gene therapy disease targets.
Details
- Title: Subtitle
- Dual therapeutic utility of proteasome modulating agents for pharmaco-gene therapy of the cystic fibrosis airway
- Creators
- Liang N ZhangZiying YanXiaoming LiuJohn F EngelhardtPhil KarpChristie P ThomasJoseph ZabnerChristopher J GerardEric PastorKeith MunsonSimon GodwinRichard PelusoBarrie CarterDouglas LauxHuidong Shi - University of MissouriCharles W Caldwell
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.10(6), pp.990-1002
- DOI
- 10.1016/j.ymthe.2004.08.009
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Language
- English
- Date published
- 2004
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pulmonary, Critical Care, and Occupational Medicine; Anatomy and Cell Biology; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Radiation Oncology; Obstetrics and Gynecology; Nephrology; Internal Medicine
- Record Identifier
- 9983985904602771
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