Ivacaftor for Acquired CFTR Dysfunction in Chronic Rhinosinusitis

The purpose of this pilot study is to explore wither ivacaftor in refractory CRS patients will demonstrate safety and tolerability; restore CFTR-mediated Cl- secretions as measured by EDSPD testing; produce detectable improvements in validated measures of CRS including the SNOT-22 questionnaire, Lund-MacKay CT scan grading, and Lund-Kennedy endoscopic scores; and provide beneficial effects on readily measured markers of sinonasal inflammation and infection (IP-10, IL-8, and Pseudomonas CFUs).

There is a significant clinical need for new treatment modalities for chronic sinus disease. Chronic rhinosinusitis (CRS) causes substantial morbidity and detracts from quality of life for 16% of the US population. The disease accrues an estimated aggregated cost of $8.6b annual in healthcare expenditures. Patients with CRS describe poorer scores for physical pain and social functioning on quality of life questionnaires than those suffering from chronic obstructive pulmonary disease (COPD), congestive heart failure, or angina. Conventional CRS treatments are comprised of antibiotics, steroids, and surgical intervention. These interventions have been limited by bacterial resistance incurred with antibiotic overuse and the deleterious side effects of steroids. Normal sinonasal mucociliary function is a vitally important host defense mechanism that clears the upper airways of inhaled particles such as bacteria, dusts, and aerosols. Sinonasal respiratory epithelium is a highly-regulated inert barrier critical to the mucociliary apparatus. Maintenance of MCC is dependent on intact respiratory epithelium, proper ciliary beating, and the biological properties of the airway surface liquid (ASL). The ASL is dramatically affected by alterations of vectorial Cl- and bicarbonate (HCO3-) secretion through the CFTR as clearly exemplified by cystic fibrosis (CF) airway disease. These abnormalities of electrolyte transport manifest as thick mucus formation and stasis of secretions in multiple organ systems, including the respiratory, gastrointestinal, and reproductive tracts. In the sinuses, chronic stasis of mucus in combination with bacterial infections results in paranasal sinusitis. Cystic fibrosis (CF) is caused by mutations in the CFTR gene. The most common cause of CF is a deletion of phenylalanine at CFTR position 508 (F508del CFTR), which confers protein misfolding and degradation from the endoplasmic reticulum. The absence of CFTR at the plasma membrane results in defective ion transport and the clinical manifestations of CF. Other mutations, such as the class III mutation Gly551Asp (G551D), result in adequate levels of CFTR protein at the apical cell surface, but exhibit defective function. In addition, there is now increasing evidence that wild type CFTR processing, endocytic recycling, and function can also be markedly compromised by various environmental insults, including cigarette smoke exposure, high altitude/hypoxemia, inflammation, and infectious agents. CFTR is a member of the ATP binding cassette protein family, and composed of two transmembrane domains (TMs), two nucleotide binding domains (NBDs), and a regulatory domain (R). Activation of CFTR is thought to be a two-step process that involves 1) phosphorylation of the R-domain, and 2) dimerization of the two NBDs, facilitating ATP binding and activation of the Cl- channel by inducing a conformational change in the TMs. One model suggests that ATP binding to the canonical catalytic site c Покажи пълното описание...

Inclusion Criteria: * 18 years of age * Patient has provided informed consent * Diagnosis of CRS made by one of the investigators * Standard of care CT scan with definitive demonstration of isolated or diffuse mucosal thickening, bone changes, and air fluid levels, obtained within 30 days of treatment * Positive culture of at least one gram negative bacteria (e.g. Pseudomonas, E. coli, Steenotrophomonas) within 30 days prior to testing * Previous surgery with (at least) exposed maxillary and ethmoid sinuses * Ability to perform EDSPD testing such that nasal cavity space and sinus openings are sufficient for catheter placement * Negative pregnancy test for females of childbearing potential within 72 hours of testing and start of study treatment Exclusion Criteria: * \< 18 years of age * Acute illness other than sinusitis within 2 weeks before start of study treatment that, in the opinion of the investigator, would preclude participation * Currently taking medications that are moderate or strong CP3A inhibitors * History of asthma attack requiring emergency room visit or treatment with oral steroids within 2 months prior to study treatment * History of solid organ or hematological transplantation * History of known immunodeficiency, autoimmune or granulomatous disorder * Serum creatinine \> 1.5x upper normal limit * Abnormal liver function, as defined by serum AST \> 2x upper normal limit, serum ALT \> 2x upper normal limit, Alkaline phosphatase \> 2x upper normal limit, Total bilirubin \> 2x upper normal limit * Women who are pregnant or breastfeeding