INCREASED SURVIVAL OF CFTR KNOCKOUT MICE WITH AN ORAL OSMOTIC LAXATIVE

Mouse models of cystic fibrosis that are generated by targeted disrupt ion (knockout) of the cystic fibrosis transmembrane conductance regula tor gene, cftr(-/-), typically die shortly after weaning, from intesti nal obstruction/rupture caused by an inability to secrete fluid into t he bowel lumen, We investigated the use of a commercial osmotic laxati ve, Colyte(R), provided continuously in the drinking water, to increas e the survival of cftr(-/-) mice, Genotype analysis of 623 offspring s urviving at 10 days of age yielded 28.1% cftr(+/+), 59.6% cftr(-/-), a nd 12.4% cftr(-/-) mice (25% predicted), suggesting that cftr(-/-) mic e have a significant perinatal mortality rate, However, of the 77 cftr (-/-) mice alive at 10 days of age, >98% survived weaning and were mai ntained in apparent health to a minimum of 56 days of age (arbitrary a ge for experimentation). In intestinal bioelectric studies Colyte(R)-t reated drinking water, compared with tap water, had no significant eff ect on basal short circuit current, cyclic AMP-stimulated Cl- secretio n, Na+-coupled glucose absorption, or electrogenic Na+ absorption acro ss intestinal sections from cftr(+/+ or +/-) mice, Other than a mild d ilatation of the distal portion of the colon in the Colyte(R)-treated animals, examination of jejunal and colonic sections revealed no histo logic differences between the two treatments, These findings indicate that the chronic use of Colyte(R) osmotic laxative in drinking water i s an economical means of greatly increasing the survival of CFTR knock out mice without altering the major electrolyte transport processes or histomorphologic integrity of the intestine.