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Cystic fibrosis therapy: a community ecology perspective.

ABSTRACT: Current therapy for cystic fibrosis (CF) focuses on minimizing the microbial community and the host's immune response through the aggressive use of airway clearance techniques, broad-spectrum antibiotics, and treatments that break down the pervasive endobronchial biofilm. Antibiotic selection is typically based on the susceptibility of individual microbial strains to specific antibiotics in vitro. Often this approach cannot accurately predict medical outcomes because of factors both technical and biological. Recent culture-independent assessments of the airway microbial and viral communities demonstrated that the CF airway infection is considerably more complex and dynamic than previously appreciated. Understanding the ecological and evolutionary pressures that shape these communities is critically important for the optimal use of current therapies (in both the choice of therapy and timing of administration) and the development of newer strategies. The climax-attack model (CAM) presented here, grounded in basic ecological principles, postulates the existence of two major functional communities. The attack community consists of transient viral and microbial populations that induce strong innate immune responses. The resultant intense immune response creates microenvironments that facilitate the establishment of a climax community that is slower-growing and inherently resistant to antibiotic therapy. Newer methodologies, including sequence-based metagenomic analysis, can track not only the taxonomic composition but also the metabolic capabilities of these changing viral and microbial communities over time. Collecting this information for CF airways will enable the mathematical modeling of microbial community dynamics during disease progression. The resultant understanding of airway communities and their effects on lung physiology will facilitate the optimization of CF therapies.

SUBMITTER: Conrad D

PROVIDER: S-EPMC3604065 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Cystic fibrosis therapy: a community ecology perspective.

Conrad Douglas D Haynes Matthew M Salamon Peter P Rainey Paul B PB Youle Merry M Rohwer Forest F

American journal of respiratory cell and molecular biology 20121025 2

Current therapy for cystic fibrosis (CF) focuses on minimizing the microbial community and the host's immune response through the aggressive use of airway clearance techniques, broad-spectrum antibiotics, and treatments that break down the pervasive endobronchial biofilm. Antibiotic selection is typically based on the susceptibility of individual microbial strains to specific antibiotics in vitro. Often this approach cannot accurately predict medical outcomes because of factors both technical an ...[more]

PMID: 23103995

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Project description:Gene therapy holds promise for the treatment of a range of inherited diseases, such as cystic fibrosis. However, efficient delivery and expression of the therapeutic transgene at levels sufficient to result in phenotypic correction of cystic fibrosis pulmonary disease has proved elusive. There are many reasons for this lack of progress, both macroscopically in terms of airway defence mechanisms and at the molecular level with regard to effective cDNA delivery. This review of approaches to cystic fibrosis gene therapy covers these areas in detail and highlights recent progress in the field. For gene therapy to be effective in patients with cystic fibrosis, the cDNA encoding the cystic fibrosis transmembrane conductance regulator protein must be delivered effectively to the nucleus of the epithelial cells lining the bronchial tree within the lungs. Expression of the transgene must be maintained at adequate levels for the lifetime of the patient, either by repeat dosage of the vector or by targeting airway stem cells. Clinical trials of gene therapy for cystic fibrosis have demonstrated proof of principle, but gene expression has been limited to 30 days at best. Results suggest that viral vectors such as adenovirus and adeno-associated virus are unsuited to repeat dosing, as the immune response reduces the effectiveness of each subsequent dose. Nonviral approaches, such as cationic liposomes, appear more suited to repeat dosing, but have been less effective. Current work regarding non-viral gene delivery is now focused on understanding the mechanisms involved in cell entry, endosomal escape and nuclear import of the transgene. There is now increasing evidence to suggest that additional ligands that facilitate endosomal escape or contain a nuclear localization signal may enhance liposome-mediated gene delivery. Much progress in this area has been informed by advances in our understanding of the mechanisms by which viruses deliver their genomes to the nuclei of host cells.

Dataset Information

Cystic fibrosis therapy: a community ecology perspective.

Publications

Cystic fibrosis therapy: a community ecology perspective.

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