Cystic Fibrosis: Using ferrets as a Disease Model.

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Presentation transcript:

Cystic Fibrosis: Using ferrets as a Disease Model

Ferret Models

Terms and Abbreviations CF = Cystic Fibrosis SCNT = Somatic Cell Nuclear Transfer MI = Meconium Ileus LFT = Liver Function Test ALT = Alanine Aminotransferase UDCA = Ursodeoxycholic Acid FABPi = Fatty acid binding promoter

Background CF affects: 1 in 3,500 newborns each year People of mixed European descent Caused by a defective CFTR gene Codes for epithelial chloride channel

Background CF affects many tissues: Lung Liver Pancreas Male Reproductive Tract Intestines Gall Bladder Sweat Gland

Why ferrets? 2 reasons: Their lung anatomy and cell biology are similar to humans They reproduce fast

Methodology Knockout gene was engineered HA-tagged cDNA of CFTR gene Used the FABPi promoter

Results 9 clones heterozygous for CFTR were bred Expected 1:2:1 ratio to create ferret models with CF, or kits

Results At 24 hours, CF kits were indestinguishable from littermates At 36 hours, they failed to thrive Euthanized at 48 hours

Results: MI Variable Penetrance MI affects the intestine It is a blockage Can cause perforations in intestine Frequency ranged for % in offspring of 9 heterzygous male parents Was statistically linked to the parents used in breeding (P< 0.047)

Results: Male RT Nearly all males with CF suffered from infertility Vas Deferens becomes absent throughout development Unilateral degeneration detected as early as 2 yrs old

Results: Male RT

Results: Pancreas All glands exhibited legions Ferrets were consistant with those in newborn humans with CF Significantly less severe than those seen on the Pig model Histopathology of gall bladder and liver indistinguishable from non CF littermates

Results: Lungs Those infants that escaped MI did not escape Lung complications 25% of neonatal deaths were not found out for those who passed MI Evidence found of pneumonia and aspiration

Results: Lungs ALT levels were elevated Bilirubin Elevated Cholesterol levels reduced Suggests potential liver disease No histo legions on liver, but elevated LFTs

Results: Liver Elevated LFTs is unclear Bile acid malabsorption by intestine Changes circulation and composition of bile acids Cholesterol levels low due to defective fatty acid absorption in the gut Oral doses of UDCA showed normalization of LFTs and ALT levels

Results: Nutrition Due to bad bile acids, lipids become hard to digest in CF patients. Due to impaired pancreas activity, HCO3- is not secreted into gut which lowers pH To counteract, oral proton pump is given to try and normalize gut pH

Conclusions There are many models out there Each one may be best suited to a specific symptom of CF Still doing research on ferrets for lungs Initial reasoning for using them is sound

References 1.) Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis Published in Volume 120, Issue 9 (September 1, 2010) J Clin Invest. 2010;120(9):3149–3160. doi: /JCI Copyright © 2010, American Society for Clinical InvestigationVolume 120, Issue 9 2.) Riordan JR, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066– ) Egan ME. How useful are cystic fibrosis mouse models? Drug Discov Today Dis Models. 2009;6(2):35–41. 4.) Rogers CS, et al. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science. 2008;321(5897):1837–1841.

All 3 Models

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