A Scientific Rationale for Using Cystic Fibrosis Transmembrane Conductance Regulator Therapeutics in COVID-19 Patients

Abstract

Several pathological manifestations in coronavirus disease 2019 (COVID-19), including thick mucus, poor mucociliary clearance, and bronchial wall thickening, overlap with cystic fibrosis disease patterns and may be indicative of “acquired” cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Indeed, tumor necrosis factor (TNF), a key cytokine driving COVID-19 pathogenesis, downregulates lung CFTR protein expression, providing a strong rationale that acquired CFTR dysfunction arises in the context of COVID-19 infection. In this perspective, we propose that CFTR therapeutics, which are safe and generally well-tolerated, may provide benefit to COVID-19 patients. Although CFTR therapeutics are currently only approved for treating cystic fibrosis, there are efforts to repurpose them for conditions with “acquired” CFTR dysfunction, for example, chronic obstructive pulmonary disease. In addition to targeting the primary lung pathology, CFTR therapeutics may possess value-added effects: their anti-inflammatory properties may dampen exaggerated immune cell responses and promote cerebrovascular dilation; the latter aspect may offer some protection against COVID-19 related stroke.

SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl− accumulation in respiratory epithelium

“…These observations indicated that abnormal CFTR function might be a key factor predisposing to the development of severe pneumonia or recalcitrant airway microbial infections, and therefore, CFTR has been hypothesized as a therapeutic target of COVID-19. 13 Here, we stimulated the RECs with the SARS-CoV-2 structural proteins to investigate whether the CFTR-Cl − signaling pathway is implicated in exuberant airway inflammation caused by SARS-CoV-2 infection, and further elucidate the underlying mechanisms.…”

A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model

“…In contrast to our data that iOWH032 inhibits CFTR, another group reported this compound can paradoxically both inhibit and potentiate human CFTR heterologously expressed in Xenopus oocytes, depending on the concentration applied [ 33 ]. The basis for these activities and their relevance to in vivo effects is unclear, but these results suggest iOWH032 could have therapeutic benefit for other diseases, including cystic fibrosis [ 34 ], influenza [ 35 ], and COVID-19 [ 36 ].…”

Application of an evidence-based, out-patient treatment strategy for COVID-19: Multidisciplinary medical practice principles to prevent severe disease

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“…Thick mucus formation can become organized in the distal bronchioles and compromise local and then general ventilation characteristics, ultimately affecting gas-exchange at the alveoli apparatus. [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]…”