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Case Western Reserve University

MOLECULAR BIOLOGY
and MICROBIOLOGY

 
 
       
 

 

Pamela B. Davis


Professor

Cystic fibrosis and gene therapy

Office Phone: 216-368-4370
Office Fax: 216.368.4223
email: pbd@case.edu


Primary Appointment: Pediatrics
     
 

Our goal is to understand the pathophysiology of cystic fibrosis (CF), a common fatal genetic disease, and to ultimately to ameliorate or cure it. One approach is to attempt to treat CF by transferring the normal gene for CFTR into the airway epithelium. We have prepared DNA nanoparticles that consist of plasmid DNA condensed with a peptide, CK30, to which has been covalently attached a molecule of polyethylene glycol. These particles are stable in tissue fluids and protect the DNA from degradation. They enter the cell via surface nucleolin, which apparently rapidly shuttles them into the nucleolus. These particles cause very few adverse effects and are effective in delivering CFTR to the airways of mice, rabbits, sheep, and humans (in the nose, in a clinical trial). Currently the nanoparticles are under development for administration by aerosol to the lung, and other indications for their use are being considered, including the potential for delivery of siRNA for therapy of viral infections. We are also considering modifications of the DNA nanoparticles to improve their cellular specificity.

A second line of work investigates consequences of CFTR dysfunction in the lung, particularly the link between CFTR and infection and inflammation. In cell and animal models, CF cells and CF mice have excessive cytokine responses to bacterial stimulation, which contributes to lung damage. We study the mechanism of this excessive response and how to prevent it without impairing host defenses. In order to identify the pathways that are different in CF, we have used both direct tests of specific hypotheses (e.g., testing the role of the anti-inflammatory PPAR system in the CF airway) and unbiased screens that include gene array analysis. Ultimately, we plan to identify therapeutic targets for clinical testing .

Selected Publications

Gene Transfer:

Rhee, M and Davis P Mechanism of uptake of C105Y-a novel cell penetrating peptide. Journal of Biological Chemistry 281:1233-40, 2006 [PubMed]

Konstan, MW, Davis, PB, Wagener, JS, Hilliard, KA, Stern, RC, Milgram, LJH Kowalczyk TH, Hyatt SL, Fink TL, Gedeon CR, Oette SM, Payne JM, Muhammad O, Ziady, AG, Moen RC,and Cooper MJ Compacted DNA Nanoparticles Administered to the Nasal Mucosa of Cystic Fibrosis Subjects are Safe and Demonstrate Partial to Complete CFTR Reconstitution, Human Gene Therapy 15:1-15, 2004 [PubMed]

Ziady AG, Kim J, Colla J, and Davis PB Defining strategies to extend duration of gene expression from targeted compacted DNA vectors. Gene Therapy 11:1378-1390, 2004 [PubMed]

Inflamation Project :

van Heeckeren, AM, Schluchter, M.D., Xue, W., Davis PB Response to acute lung infection with mucoid Pseudomonas aeruginosa in cystic fibrosis mice, Am J Resp Crit Care Med. 173:288-296, 2006 [PubMed]

Kube, D., Fletcher, D. and Davis, P.B. Relation of exaggerated cytokine responses of CF airway epithelial cells to PAO1 adherence. Respir Res. 2005 Jul 11;6(1):69 [PubMed]

van Heeckeren AM Schluchter, MD Davis, PB Role of Cftr Genotype in the Response to Chronic Pseudomonas aeruginosa Lung Infection in Mice Am J. Physiology:Lung Cell and Molecular Physiology 2004 ;287(5):L944-52. [PubMed]

Complete list of Publications