ABSTRACT
Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTR G551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTR G551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.
Subject(s)
Aminophenols/administration & dosage , Chloride Channel Agonists/administration & dosage , Cystic Fibrosis/drug therapy , Quinolones/administration & dosage , Animals , Animals, Genetically Modified , Animals, Newborn , Blood Glucose/metabolism , Cystic Fibrosis/genetics , Cystic Fibrosis/physiopathology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Disease Models, Animal , Disease Progression , Female , Ferrets , Gene Knock-In Techniques , Genitalia, Male/abnormalities , Genitalia, Male/drug effects , Gestational Age , Humans , Male , Mutation , Pancreas, Exocrine/drug effects , Pancreas, Exocrine/pathology , Pancreas, Exocrine/physiopathology , Pregnancy , Respiratory Tract Infections/etiology , Respiratory Tract Infections/prevention & control , Translational Research, BiomedicalABSTRACT
The antinociceptive and analgesic effects of muscarinic receptor ligands in human and nonhuman species have been evident for more than half a century. In this review, we describe the current understanding of the roles of different muscarinic subtypes in pain modulation and their mechanism of action along the pain signaling pathway, including peripheral nociception, spinal cord pain processing, and supraspinal analgesia. Extensive preclinical and clinical validation of these mechanisms points to the development of selective muscarinic agonists as one of the most exciting and promising avenues toward novel pain medications.
