Pamela Davis
Professor
Devising new treatments for cystic fibrosis
RESEARCH DESCRIPTION
Our goal is to understand the pathophysiology of cystic fibrosis (CF), a common fatal genetic disease, and ultimately to ameliorate or cure it. CF is caused by defects in a gene that encodes a chloride channel, CFTR, but patients succumb to pulmonary infection and inflammation. We investigate how dysfunction of CFTR leads to infection and excess inflammation. CF airway epithelial cells and CF mice model the excessive cytokine responses to bacterial stimulation, and we are studying the mechanism of the response and how to prevent it without impairing host defenses. We found before that high dose ibuprofen ameliorates the excessive inflammation clinically. Our current working hypothesis is that ibuprofen works by binding to PPAR-?, a nuclear receptor which can interact with the pro-inflammatory transcription factor NF-?B to inhibit it. Ultimately, we will build upon our findings in cell and animal models for design of a clinical trial. A second line of work is to devise means to deliver normal CFTR gene to the airways of patients. We construct DNA nanoparticles that consist of plasmid DNA compacted with polylysine, stabilized with polyethylene glycol. Their small size allows nuclear access in nondividing cells. These nanoparticles can transfect airway epithelium in vivo in CF mice to correct not only the CF chloride transport defect but also some of its downstream consequences. In addition, these nanoparticles are nontoxic, and can be dosed repeatedly. A single-dose Phase I clinical trial in the nose of human patients with CF was completed, and 8 of 12 subjects had improvement in chloride transport, with no adverse effects attributable to drug. Current work is investigating improvements in the DNA nanoparticles (including targeting and improvement of the plasmid construct), aerosolization of the particles for pulmonary treatment, and extension of the molecular targets to delivery of siRNA directed against respiratory viruses.
RELATED RESEARCH AREAS
View Pamela Davis's Publications on PubMed
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Cleveland, Ohio 44106-4970 
