Publications by authors named "Steven M Rowe"

189 Publications

Effect of lumacaftor-ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis: Results from the PROSPECT MCC sub-study.

J Cyst Fibros 2021 May 31. Epub 2021 May 31.

Department of Medicine and the Marsico Lung Institute, University of North Carolina at Chapel Hill, 2204 Marsico Hall, CB#7248, 125 Mason Farm Road, Chapel Hill, NC 27514, United States.

CFTR function is required for normal mucociliary clearance (MCC) and cough-assisted clearance (CC). Lumacaftor-ivacaftor is approved for use in people with cystic fibrosis (CF) carrying two copies of F508del-CFTR. In this observational study performed at four study sites, we characterized the effect of lumacaftor-ivacaftor on mucociliary and cough clearance and related this to other clinical and research endpoints after one month of treatment. Twenty-five adolescents and adults were enrolled. No effect on whole lung MCC was observed, but CC was significantly increased. Sweat chloride improved by 18 mEq/L in this group, indicating a modest restoration of CFTR activity, but no demonstrable change in FEV or lung clearance index was observed. We speculate that the modest effect of lumacaftor-ivacaftor on CFTR function was insufficient to yield an improvement in MCC.
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http://dx.doi.org/10.1016/j.jcf.2021.05.004DOI Listing
May 2021

LPS decreases CFTR open probability and mucociliary transport through generation of reactive oxygen species.

Redox Biol 2021 Jul 30;43:101998. Epub 2021 Apr 30.

Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Lipopolysaccharide (LPS) serves as the interface between gram-negative bacteria (GNB) and the innate immune response in respiratory epithelial cells (REC). Herein, we describe a novel biological role of LPS that permits GNB to persist in the respiratory tract through inducing CFTR and mucociliary dysfunction. LPS reduced cystic fibrosis transmembrane conductance regulater (CFTR)-mediated short-circuit current in mammalian REC in Ussing chambers and nearly abrogated CFTR single channel activity (defined as forskolin-activated Cl currents) in patch clamp studies, effects of which were blocked with toll-like receptor (TLR)-4 inhibitor. Unitary conductance and single-channel amplitude of CFTR were unaffected, but open probability and number of active channels were markedly decreased. LPS increased cytoplasmic and mitochondrial reactive oxygen species resulting in CFTR carbonylation. All effects of exposure were eliminated when reduced glutathione was added in the medium along with LPS. Functional microanatomy parameters, including mucociliary transport, in human sinonasal epithelial cells in vitro were also decreased, but restored with co-incubation with glutathione or TLR-4 inhibitor. In vivo measurements, following application of LPS in the nasal cavities showed significant decreases in transepithelial Cl secretion as measured by nasal potential difference (NPD) - an effect that was nullified with glutathione and TLR-4 inhibitor. These data provide definitive evidence that LPS-generated reactive intermediates downregulate CFTR function in vitro and in vivo which results in cystic fibrosis-type disease. Findings have implications for therapeutic approaches intent on stimulating Cl secretion and/or reducing oxidative stress to decrease the sequelae of GNB airway colonization and infection.
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http://dx.doi.org/10.1016/j.redox.2021.101998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129928PMC
July 2021

A Phase 3 Open-Label Study of ELX/TEZ/IVA in Children 6 Through 11 Years of Age With CF and at Least One Allele.

Am J Respir Crit Care Med 2021 Mar 18. Epub 2021 Mar 18.

Ann & Robert H. Lurie Children's Hospital of Chicago, Pulmonary Medicine, Chicago, Illinois, United States.

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients aged 12 years and older with cystic fibrosis and at least one F508del-CFTR allele, but has not been evaluated in children <12 years of age.

Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes.

Methods: In this 24-week open-label Phase 3 study, children (N=66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours) while children weighing ≥30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours).

Measurements And Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most common reported adverse events (AEs) included cough, headache, and pyrexia; in most of the children who had AEs, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the ppFEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period compared to the pre-treatment baseline.

Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03691779 This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202102-0509OCDOI Listing
March 2021

PROMISE: Working with the CF community to understand emerging clinical and research needs for those treated with highly effective CFTR modulator therapy.

J Cyst Fibros 2021 Mar 19;20(2):205-212. Epub 2021 Feb 19.

Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.
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http://dx.doi.org/10.1016/j.jcf.2021.02.003DOI Listing
March 2021

Novel Correctors and Potentiators Enhance Translational Readthrough in CFTR Nonsense Mutations.

Am J Respir Cell Mol Biol 2021 May;64(5):604-616

Department of Medicine.

Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) result in nonfunctional CFTR protein and are the proximate cause of ∼11% of CF-causing alleles, for which no treatments exist. The CFTR corrector lumacaftor and the potentiator ivacaftor improve CFTR function with terminal PTC mutations and enhance the effect of readthrough agents. Novel correctors GLPG2222 (corrector 1 [C1]), GLPG3221 (corrector 2 [C2]), and potentiator GLPG1837 compare favorably with lumacaftor and ivacaftor . Here, we evaluated the effect of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in combination with the readthrough compound G418 on CFTR function using heterologous Fischer rat thyroid (FRT) cells, the genetically engineered human bronchial epithelial (HBE) 16HBE14o cell lines, and primary human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded those from ivacaftor in FRT-W1282X and FRT-R1162X cells. A three-mechanism strategy consisting of G418, GLPG1837, and two correctors (C1a + C2a) yielded the greatest functional improvements in FRT and 16HBE14o PTC variants, noting that correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X cells. GLPG1837 + C1a + C2a restored substantial function in G542X/F508del HBE cells and restored even more function for W1282X/F508del cells, largely because of the corrector/potentiator effect, with no additional benefit from G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin-induced swelling was observed with G418 + GLPG1837 + C1a + C2a, although GLPG1837 + C1a + C2a alone was sufficient to improve forskolin-induced swelling in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators, and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR.
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http://dx.doi.org/10.1165/rcmb.2019-0291OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086047PMC
May 2021

Measuring the impact of CFTR modulation on sweat chloride in cystic fibrosis: Rationale and design of the CHEC-SC study.

J Cyst Fibros 2021 Feb 8. Epub 2021 Feb 8.

Seattle Children's Research Institute, Seattle, WA 98145, USA; Department of Biostatistics and Pediatrics, University of Washington, Seattle, WA 98195, USA.

Background: The Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes (CHEC-SC) study is a large epidemiologic study designed to determine the relationship between sweat chloride response and clinical outcomes in people with cystic fibrosis (CF) on commercially approved CFTR modulators. A challenge to study feasibility was capturing sweat chloride measurements before modulator initiation. We tested the hypothesis that historic sweat chloride approximated contemporary pre-modulator values to estimate CFTR modulator-induced changes, allowing a single-visit study design.

Methods: GOAL and PROSPECT were multi-center prospective studies of individuals initiating ivacaftor or lumacaftor-ivacaftor. At enrollment, pre-modulator sweat chloride was measured and historic results recorded. Post-modulator sweat chloride was measured at 1, 3 and 6 months. For this analysis, differences between historic and pre-modulator sweat chloride were estimated. CFTR modulator-induced sweat chloride mean changes were compared using historic and pre-modulator sweat chloride.

Results: Paired historic and pre-modulator sweat chloride (n=406 participants) revealed a non-significant mean change of -1.0 mmol/L (95% CI: -2.71, 0.66) over an average of 17.2 years. Calculating sweat response to ivacaftor or lumacaftor-ivacaftor using historic or pre-modulator values resulted in similar estimates of modulator response. Based on these results, the CHEC-SC study was designed with a single, post-modulator sweat chloride measurement.

Conclusions: Historic sweat chloride values provide a reliable estimate of pre-modulator sweat chloride for people starting on modulator therapy. The CHEC-SC study anticipates capturing approximately 5,000 sweat chloride values, providing an unprecedented understanding of sweat chloride across the CF population in the era of CFTR modulators.
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http://dx.doi.org/10.1016/j.jcf.2021.01.011DOI Listing
February 2021

Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study.

Respir Res 2021 Feb 1;22(1):30. Epub 2021 Feb 1.

Division of Intramural Research, National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, NC, 27709, USA.

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) carry significant morbidity and mortality. AECOPD treatment remains limited. High molecular weight hyaluronan (HMW-HA) is a glycosaminoglycan sugar, which is a physiological constituent of the lung extracellular matrix and has notable anti-inflammatory and hydrating properties.

Research Question: We hypothesized that inhaled HMW-HA will improve outcomes in AECOPD.

Methods: We conducted a single center, randomized, placebo-controlled, double-blind study to investigate the effect of inhaled HMW-HA in patients with severe AECOPD necessitating non-invasive positive-pressure ventilation (NIPPV). Primary endpoint was time until liberation from NIPPV.

Results: Out of 44 screened patients, 41 were included in the study (21 for placebo and 20 for HMW-HA). Patients treated with HMW-HA had significantly shorter duration of NIPPV. HMW-HA treated patients also had lower measured peak airway pressures on the ventilator and lower systemic inflammation markers after liberation from NIPPV. In vitro testing showed that HMW-HA significantly improved mucociliary transport in air-liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract.

Interpretation: Inhaled HMW-HA shortens the duration of respiratory failure and need for non-invasive ventilation in patients with AECOPD. Beneficial effects of HMW-HA on mucociliary clearance and inflammation may account for some of the effects (NCT02674880, www.clinicaltrials.gov ).
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http://dx.doi.org/10.1186/s12931-020-01610-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847749PMC
February 2021

Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion.

J Ginseng Res 2021 Jan 13;45(1):66-74. Epub 2019 Sep 13.

Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States.

Background: Abnormal chloride (Cl) transport has a detrimental impact on mucociliary clearance in both cystic fibrosis (CF) and non-CF chronic rhinosinusitis. Ginseng is a medicinal plant noted to have anti-inflammatory and antimicrobial properties. The present study aims to assess the capability of red ginseng aqueous extract (RGAE) to promote transepithelial Cl secretion in nasal epithelium.

Methods: Primary murine nasal septal epithelial (MNSE) [wild-type (WT) and transgenic CFTR], fisher-rat-thyroid (FRT) cells expressing human WT CFTR, and TMEM16A-expressing human embryonic kidney cultures were utilized for the present experiments. Ciliary beat frequency (CBF) and airway surface liquid (ASL) depth measurements were performed using micro-optical coherence tomography (μOCT). Mechanisms underlying transepithelial Cl transport were determined using pharmacologic manipulation in Ussing chambers and whole-cell patch clamp analysis.

Results: RGAE (at 30μg/mL of ginsenosides) significantly increased Cl transport [measured as change in short-circuit current (ΔI = μA/cm)] when compared with control in WT and CFTR MNSE (WT vs control = 49.8±2.6 vs 0.1+/-0.2, CFTR = 33.5±1.5 vs 0.2±0.3, p < 0.0001). In FRT cells, the CFTR-mediated ΔI attributed to RGAE was small (6.8 ± 2.5 vs control, 0.03 ± 0.01, p < 0.05). In patch clamp, TMEM16A-mediated currents were markedly improved with co-administration of RGAE and uridine 5-triphosphate (8406.3 +/- 807.7 pA) over uridine 5-triphosphate (3524.1 +/- 292.4 pA) or RGAE alone (465.2 +/- 90.7 pA) (p < 0.0001). ASL and CBF were significantly greater with RGAE (6.2+/-0.3 m vs control, 3.9+/-0.09 m; 10.4+/-0.3 Hz vs control, 7.3 ± 0.2 Hz;  < 0.0001) in MNSE.

Conclusion: RGAE augments ASL depth and CBF by stimulating Cl secretion through CaCC, which suggests therapeutic potential in both CF and non-CF chronic rhinosinusitis.
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http://dx.doi.org/10.1016/j.jgr.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790903PMC
January 2021

A Novel G542X CFTR Rat Model of Cystic Fibrosis Is Sensitive to Nonsense Mediated Decay.

Front Physiol 2020 16;11:611294. Epub 2020 Dec 16.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.

Nonsense mutations that lead to the insertion of a premature termination codon (PTC) in the cystic fibrosis transmembrane conductance regulator (CFTR) transcript affect 11% of patients with cystic fibrosis (CF) worldwide and are associated with severe disease phenotype. While CF rat models have contributed significantly to our understanding of CF disease pathogenesis, there are currently no rat models available for studying CF nonsense mutations. Here we created and characterized the first homozygous CF rat model that bears the CFTR G542X nonsense mutation in the endogenous locus using CRISPR/Cas9 gene editing. In addition to displaying severe CF manifestations and developmental defects such as reduced growth, abnormal tooth enamel, and intestinal obstruction, CFTR G542X knockin rats demonstrated an absence of CFTR function in tracheal and intestinal sections as assessed by nasal potential difference and transepithelial short-circuit current measurements. Reduced CFTR mRNA levels in the model further suggested sensitivity to nonsense-mediated decay, a pathway elicited by the presence of PTCs that degrades the PTC-bearing transcripts and thus further diminishes the level of CFTR protein. Although functional restoration of CFTR was observed in G542X rat tracheal epithelial cells in response to single readthrough agent therapy, therapeutic efficacy was not observed in G542X knockin rats . The G542X rat model provides an invaluable tool for the identification and validation of potential therapies for CFTR nonsense mutations.
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http://dx.doi.org/10.3389/fphys.2020.611294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772197PMC
December 2020

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251).

J Cyst Fibros 2021 Mar 6;20(2):250-256. Epub 2020 Dec 6.

Novartis Institutes for BioMedical Research, Cambridge, MA, United States; Novartis Institutes for BioMedical Research, Basel, Switzerland.

Background: This is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.

Methods: Safety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI). Secondary endpoints included %predicted FEV and sweat chloride level.

Results: Class IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV increased by 6.46%, LCI decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.

Conclusions: Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations. ClinicalTrials.gov: NCT02190604.
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http://dx.doi.org/10.1016/j.jcf.2020.11.002DOI Listing
March 2021

Gaming Console Home-Based Exercise for Adults with Cystic Fibrosis: Study Protocol.

Int J Caring Sci 2020 Spring/Summer;13(2):1530-1540

Department of Occupational Therapy, School of Health Professions, University of Alabama at Birmingham, 1720 2nd Ave S, Birmingham, AL, USA.

Background: Despite evidence of exercise benefits to lung function, adherence to routine exercise in adults with cystic fibrosis (CF) is low. The incorporation of interactive virtual reality video exergame activities in home-based programs as an incentive may help improve motivation and adherence to exercise. This proposed study will attempt to improve the physical fitness and respiratory function of sedentary adults with CF by engaging them in a Nintendo Wii Fit Plus™ home-based exercise program.

Methods: A single group pretest-posttest design will be used to examine the immediate (12-weeks) and long-term effect (24-weeks) of a home-based exergame program on improving pulmonary-related function (physical fitness and respiratory function) in sedentary adults with CF. Participants will receive a one-time orientation to the Wii Fit Plus, and will be requested to use it to exercise according to the recommended guidelines 3 times a week for 30 min in the following 24 weeks. Monthly phone monitoring will be conducted during the first 12 weeks. Besides evaluating the efficacy of a home-based exergame program on improving aerobic capacity, physical activity, and respiratory-related symptoms, we will examine the impact of the exergame on airway ion transport as measured by nasal potential difference, which will be collected at baseline and at the end of 12-weeks only.

Discussion: This is the first study to evaluate the feasibility, acceptability and potential effectiveness of a low-cost exercise avenue (i.e., exergames) for adults with CF to improve their pulmonary-related function, which is important for CF disease management and prevention of complications. In addition, the proposed study will be the first to investigate the therapeutic efficacy of home-based exergames on airway ion transport among adults with CF. Through an increase in physical activity, it is expected that participants will improve their physical fitness and respiratory function at the end of the study.

Trial Registration: ClinicalTrials.gov ID: NCT02277860.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643879PMC
November 2020

Efficacy and Safety of the CFTR Potentiator Icenticaftor (QBW251) in COPD: Results from a Phase 2 Randomized Trial.

Int J Chron Obstruct Pulmon Dis 2020 5;15:2399-2409. Epub 2020 Oct 5.

Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

Rationale: Excess mucus plays a key role in COPD pathogenesis. Cigarette smoke-induced cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction may contribute to disease pathogenesis by depleting airway surface liquid and reducing mucociliary transport; these defects can be corrected in vitro by potentiating CFTR.

Objective: To assess the efficacy of the CFTR potentiator icenticaftor in improving airflow obstruction in COPD patients with symptoms of chronic bronchitis.

Methods: In this double-blind, placebo-controlled study, COPD patients were randomized (2:1) to either icenticaftor 300 mg or placebo b.i.d. This non-confirmatory proof of concept study was powered for lung clearance index (LCI) and pre-bronchodilator FEV, with an estimated sample size of 90 patients. The primary endpoint was change from baseline in LCI for icenticaftor versus placebo at Day 29; key secondary endpoints included change from baseline in pre- and post-bronchodilator FEV on Day 29. Key exploratory endpoints included change from baseline in sweat chloride, plasma fibrinogen levels, and sputum colonization.

Results: Ninety-two patients were randomized (icenticaftor, n=64; placebo, n=28). At Day 29, icenticaftor showed no improvement in change in LCI (treatment difference: 0.28 [19% probability of being better than placebo]), an improvement in pre-bronchodilator FEV (mean: 50 mL [84% probability]) and an improvement in post-bronchodilator FEV (mean: 63 mL [91% probability]) over placebo. Improvements in sweat chloride, fibrinogen and sputum bacterial colonization were also observed. Icenticaftor was safe and well tolerated.

Conclusion: The CFTR potentiator icenticaftor increased FEV versus placebo after 28 days and was associated with improvements in systemic inflammation and sputum bacterial colonization in COPD patients; no improvements in LCI with icenticaftor were observed.
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http://dx.doi.org/10.2147/COPD.S257474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547289PMC
October 2020

Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis.

J Cyst Fibros 2020 Oct 3. Epub 2020 Oct 3.

University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Objectives: Tobacco smoke exposure reduces CFTR functional expression in vitro and contributes to acquired CFTR dysfunction. We investigated whether it also inhibits the clinical benefit of CFTR modulators, focusing on tezacaftor/ivacaftor, approved in February 2018 for individuals with CF age ≥12 years.

Methods: A retrospective longitudinal analysis of encounter-based data from the CF Foundation Patient Registry (2016-2018) compared the slope of change in lung function (GLI FEV% predicted) before and after tezacaftor/ivacaftor initiation in smoke-exposed vs unexposed age-eligible pediatric patients. Tobacco smoke exposure (Ever/Never) was determined from caregiver self-report. Statistical analyses used hierarchical linear mixed modeling and fixed effects regression modeling.

Results: The sample included 6,653 individuals with a total of 105,539 person-period observations. Tezacaftor/ivacaftor was prescribed to 19% (1,251) of individuals, mean age 17 years, mean baseline ppFEV 83%, 28% smoke-exposed. Tezacaftor/ivacaftor users who were smoke-exposed had a lower baseline ppFEV and experienced a greater lung function decline. Over two years, the difference in ppFEV by smoke exposure among tezacaftor/ivacaftor users increased by 1.2% (7.6% to 8.8%, p<0.001). In both mixed effects and fixed effects regression models, tezacaftor/ivacaftor use was associated with improved ppFEV among unexposed individuals (1.2% and 1.7%, respectively; p<0.001 for both) but provided no benefit among smoke-exposed counterparts (0.3%, p = 0.5 and 0.6%, p = 0.07, respectively).

Conclusion: Tobacco smoke exposure nullifies the therapeutic benefit of tezacaftor/ivacaftor among individuals with CF aged 12-20 years old. To maximize the therapeutic opportunity of CFTR modulators, every effort must be taken to eliminate smoke exposure in CF.
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http://dx.doi.org/10.1016/j.jcf.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018981PMC
October 2020

Lumacaftor/ivacaftor therapy fails to increase insulin secretion in F508del/F508del CF patients.

J Cyst Fibros 2021 Mar 8;20(2):333-338. Epub 2020 Sep 8.

Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States. Electronic address:

Background: Glucose tolerance abnormalities including cystic fibrosis related diabetes (CFRD) are common in patients with cystic fibrosis (CF). The underlying pathophysiology is not fully understood. Emerging evidence suggests that CFTR dysfunction may directly or indirectly impact β-cell function, offering the potential for improvement with CFTR modulator therapy. In small pilot studies, treatment with ivacaftor improved insulin secretion in patients with the G551D CFTR mutation. In the current study, we examined the impact of lumacaftor/ivacaftor therapy on glucose tolerance and insulin secretion in patients with CF who were homozygous for the F508del mutation.

Methods: 39 subjects from the PROSPECT Part B study who had been prescribed lumacaftor/ivacaftor by their CF care team at a CF Foundation's Therapeutic Development Network center were recruited. Subjects underwent 2-hour oral glucose tolerance tests (OGTTs) at baseline prior to first dose of lumacaftor/ivacaftor, and at 3, 6 and 12 months on therapy. OGTT glucose, insulin and c-peptide parameters were compared.

Results: Compared to baseline, OGTT fasting and 2 hour glucose levels, glucose area under the curve, insulin area under the curve and time to peak insulin level were not significantly different at 3, 6 and 12 months on lumacaftor/ivacaftor therapy. Similarly, C-peptide levels were no different.

Conclusions: Lumacaftor/ivacaftor therapy did not improve insulin secretion or glucose tolerance in patients with CF who were homozygous for the F508del mutation.
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http://dx.doi.org/10.1016/j.jcf.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937760PMC
March 2021

G551D mutation impairs PKA-dependent activation of CFTR channel that can be restored by novel GOF mutations.

Am J Physiol Lung Cell Mol Physiol 2020 11 2;319(5):L770-L785. Epub 2020 Sep 2.

Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.

G551D is a major disease-associated gating mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP- and phosphorylation-dependent chloride channel. G551D causes severe cystic fibrosis (CF) disease by disrupting ATP-dependent channel opening; however, whether G551D affects phosphorylation-dependent channel activation is unclear. Here, we use macropatch recording and Ussing chamber approaches to demonstrate that G551D impacts on phosphorylation-dependent activation of CFTR, and PKA-mediated phosphorylation regulates the interaction between the x-loop in nucleotide-binding domain 2 (NBD2) and cytosolic loop (CL) 1. We show that G551D not only disrupts ATP-dependent channel opening but also impairs phosphorylation-dependent channel activation by largely reducing PKA sensitivity consistent with the reciprocal relationship between channel opening/gating, ligand binding, and phosphorylation. Furthermore, we identified two novel GOF mutations: D1341R in the x-loop near the ATP-binding cassette signature motif in NBD2 and D173R in CL1, each of which strongly increased PKA sensitivity both in the wild-type (WT) background and when introduced into G551D-CFTR. When D1341R was combined with a second GOF mutation (e.g., K978C in CL3), we find that the double GOF mutation maximally increased G551D channel activity such that VX-770 had no further effect. We further show that a double charge-reversal mutation of D1341R/D173R-CFTR exhibited similar PKA sensitivity when compared with WT-CFTR. Together, our results suggest that charge repulsion between D173 and D1341 of WT-CFTR normally inhibits channel activation at low PKA activity by reducing PKA sensitivity, and negative allostery by the G551D is coupled to reduced PKA sensitivity of CFTR that can be restored by second GOF mutations.
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http://dx.doi.org/10.1152/ajplung.00262.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701354PMC
November 2020

Contribution of Short Chain Fatty Acids to the Growth of in Rhinosinusitis.

Front Cell Infect Microbiol 2020 11;10:412. Epub 2020 Aug 11.

Department of Otolaryngology Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL, United States.

Chronic rhinosinusitis (CRS) is characterized by complex bacterial infections with persistent inflammation. Based on our rabbit model of sinusitis, blockage of sinus ostia generated a shift in microbiota to a predominance of mucin degrading microbes (MDM) with acute inflammation at 2 weeks. This was followed by conversion to chronic sinus inflammation at 3 months with a robust increase in pathogenic bacteria (e.g., ). MDMs are known to produce acid metabolites [short chain fatty acids (SCFA)] that have the potential to stimulate pathogen growth by offering a carbon source to non-fermenting sinus pathogens (e.g., ). The objective of this study is to evaluate the concentrations of SCFA within the mucus and its contribution to the growth of . Healthy and sinusitis mucus from the rabbit model were collected and co-cultured with the PAO1 strain of for 72 h and colony forming units (CFUs) were determined with the targeted quantification of three SCFAs (acetate, propionate, butyrate). Quantification of SCFAs in healthy and sinusitis mucus from patients with was also performed via high performance liquid chromatography. To provide evidence of fermentative activity, SCFAs were quantified within the mucus samples from rabbits with and without sinusitis. Acetate concentrations were significantly greater in sinusitis mucus compared to controls (4.13 ± 0.53 vs. 1.94 ± 0.44 mM, < 0.01). After 72 h of co-culturing mucus samples with PAO1 in the presence of mucin medium, the blue-green pigment characteristic of was observed throughout tubes containing sinusitis mucus. CFUs were higher in cultures containing mucus samples from sinusitis (8.4 × 10 ± 4.8 × 10) compared to control (1.4 × 10 ± 2.0 × 10) or no mucus (1.5 × 10 ± 2.1 × 10) ( < 0.0001). To provide evidence of fermentative activity in human CRS with , the presence of SCFAs in human mucus was analyzed and all SCFAs were significantly higher in CRS with compared to controls ( < 0.05). Given that SCFAs are solely derived from bacterial fermentation, our evidence suggests a critical role for mucin-degrading bacteria in generating carbon-source nutrients for pathogens. MDM may contribute to the development of recalcitrant CRS by degrading mucins, thus providing nutrients for potential pathogens like .
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http://dx.doi.org/10.3389/fcimb.2020.00412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431473PMC
August 2020

persists in biofilm communities in a smoke-exposed ferret model of COPD.

ERJ Open Res 2020 Jul 11;6(3). Epub 2020 Aug 11.

Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.

Rationale: Non-typeable (NTHi) is a common inhabitant of the human nasopharynx and upper airways that can cause opportunistic infections of the airway mucosa including bronchopulmonary infections in patients with chronic obstructive pulmonary disease (COPD). It is clear that opportunistic infections contribute significantly to inflammatory exacerbations of COPD; however, there remains much to be learned regarding specific host and microbial determinants of persistence and/or clearance in this context.

Methods: In this study, we used a recently described ferret model for COPD, in which animals undergo chronic long-term exposure to cigarette smoke, to define host-pathogen interactions during COPD-related NTHi infections.

Results: NTHi bacteria colonised the lungs of smoke-exposed animals to a greater extent than controls, and elicited acute host inflammation and neutrophilic influx and activation, along with a significant increase in airway resistance and a decrease in inspiratory capacity consistent with inflammatory exacerbation; notably, these findings were not observed in air-exposed control animals. NTHi bacteria persisted within multicellular biofilm communities within the airway lumen, as evidenced by immunofluorescent detection of bacterial aggregates encased within a sialylated matrix as is typical of NTHi biofilms and differential bacterial gene expression consistent with the biofilm mode of growth.

Conclusions: Based on these results, we conclude that acute infection with NTHi initiates inflammatory exacerbation of COPD disease. The data also support the widely held hypothesis that NTHi bacteria persist within multicellular biofilm communities in the lungs of patients with COPD.
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http://dx.doi.org/10.1183/23120541.00200-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418822PMC
July 2020

Fibroblast Growth Factor Receptor 4 Deficiency Mediates Airway Inflammation in the Adult Healthy Lung?

Front Med (Lausanne) 2020 24;7:317. Epub 2020 Jul 24.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States.

Fibroblast growth factor receptor (FGFR) 4 has been shown to mediate pro-inflammatory signaling in the liver and airway epithelium in chronic obstructive pulmonary disease. In past reports, FGFR4 knockout ( mice did not show any lung phenotype developmentally or at birth, unless FGFR3 deficiency was present simultaneously. Therefore, we wanted to know whether the loss of FGFR4 had any effect on the adult murine lung. Our results indicate that adult mice demonstrate a lung phenotype consisting of widened airway spaces, increased airway inflammation, bronchial obstruction, and right ventricular hypertrophy consistent with emphysema. Despite downregulation of FGF23 serum levels, interleukin (IL) 1β and IL-6 in the lung, and abrogation of p38 signaling, primary murine airway cells showed increased expression of IL-1β and augmented secretion of IL-6, which correlated with decreased airway surface liquid depth as assessed by micro-optical coherence tomography. These findings were paralleled by increased ERK phosphorylation in airway cells when compared with their control wild-type cells. Analysis of a murine model with constitutive activation of FGFR4 showed attenuation of pro-inflammatory mediators in the lung and airway epithelium. In conclusion, we are the first to show an inflammatory and obstructive airway phenotype in the adult healthy murine lung, which might be due to the upregulation of ERK phosphorylation in the airway epithelium.
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http://dx.doi.org/10.3389/fmed.2020.00317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393220PMC
July 2020

Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial.

Ann Am Thorac Soc 2021 01;18(1):75-83

Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama.

The combination of lumacaftor (LUM) and ivacaftor (IVA) is an approved CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator treatment for homozygous F508del patients with CF. To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting. This longitudinal cohort study, performed at 38 centers in the U.S. CF Therapeutics Development Network, enrolled homozygous F508del patients with CF ages 6 years old and older with no prior exposure to LUM/IVA. Study assessments were performed at baseline and at 1, 3, 6, and 12 months after LUM/IVA initiation. A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m;  < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3;  < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and infection status with treatment. In this real-world multicenter cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or infection.Clinical trial registered with www.clinicaltrials.gov (NCT02477319).
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http://dx.doi.org/10.1513/AnnalsATS.202002-144OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780982PMC
January 2021

Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events.

J Cyst Fibros 2021 Mar 23;20(2):228-233. Epub 2020 Jun 23.

Vertex Pharmaceuticals Incorporated, Boston, MA, USA.

Background: Increased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.

Methods: Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.

Results: Of 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.

Conclusions: Tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.
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http://dx.doi.org/10.1016/j.jcf.2020.06.001DOI Listing
March 2021

Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR.

Am J Respir Crit Care Med 2020 11;202(9):1271-1282

Department of Medicine.

Animal models have been highly informative for understanding the characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR rat has revealed insights into the airway mucus defect characteristic of CF but does not replicate a human-relevant CFTR (cystic fibrosis transmembrane conductance regulator) variant. We hypothesized that a rat expressing a humanized version of CFTR and harboring the ivacaftor-sensitive variant G551D could be used to test the impact of CFTR modulators on pathophysiologic development and correction. In this study, we describe a humanized-CFTR rat expressing the G551D variant obtained by zinc finger nuclease editing of a human complementary DNA superexon, spanning exon 2-27, with a 5' insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared with wild-type animals. The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity, were normalized after the administration of ivacaftor. This model is useful to understand the mechanisms of disease and the extent of pathology reversal with CFTR modulators.
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http://dx.doi.org/10.1164/rccm.202002-0369OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605185PMC
November 2020

CFTR targeted therapies: recent advances in cystic fibrosis and possibilities in other diseases of the airways.

Eur Respir Rev 2020 Jun 16;29(156). Epub 2020 Jun 16.

Dept of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion transporter that regulates mucus hydration, viscosity and acidity of the airway epithelial surface. Genetic defects in impair regulation of mucus homeostasis, causing severe defects of mucociliary clearance as seen in cystic fibrosis. Recent work has established that CFTR dysfunction can be acquired in chronic obstructive pulmonary disease (COPD) and may also contribute to other diseases that share clinical features of cystic fibrosis, such as asthma, allergic bronchopulmonary aspergillosis and bronchiectasis. Protean causes of CFTR dysfunction have been identified including cigarette smoke exposure, toxic metals and downstream effects of neutrophil activation pathways. Recently, CFTR modulators, small molecule agents that potentiate CFTR or restore diminished protein levels at the cell surface, have been successfully developed for various gene defects, prompting interest in their use to treat diseases of acquired dysfunction. The spectrum of CFTR dysfunction, strategies for CFTR modulation, and candidate diseases for CFTR modulation beyond cystic fibrosis will be reviewed in this manuscript.
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http://dx.doi.org/10.1183/16000617.0068-2019DOI Listing
June 2020

Brd4-p300 inhibition downregulates Nox4 and accelerates lung fibrosis resolution in aged mice.

JCI Insight 2020 07 23;5(14). Epub 2020 Jul 23.

Tissue regeneration capacity declines with aging in association with heightened oxidative stress. Expression of the oxidant-generating enzyme, NADPH oxidase 4 (Nox4), is elevated in aged mice with diminished capacity for fibrosis resolution. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal (BET) family of proteins that function as epigenetic "readers" of acetylated lysine groups on histones. In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. BET inhibition interferes with the association of Brd4, p300, and acetylated histone H4K16 with the Nox4 promoter in lung fibroblasts stimulated with the profibrotic cytokine, TGF-β1. A number of BET inhibitors, including I-BET-762, JQ1, and OTX015, downregulate Nox4 gene expression and activity. Aged mice with established and persistent lung fibrosis recover capacity for fibrosis resolution with OTX015 treatment. This study implicates epigenetic regulation of Nox4 by Brd4 and p300 and supports BET/Brd4 inhibition as an effective strategy for the treatment of age-related fibrotic lung disease.
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http://dx.doi.org/10.1172/jci.insight.137127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453889PMC
July 2020

Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study.

J Cyst Fibros 2020 11 6;19(6):931-933. Epub 2020 Jun 6.

Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.

The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.
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http://dx.doi.org/10.1016/j.jcf.2020.05.010DOI Listing
November 2020

Pharmacological approaches for targeting cystic fibrosis nonsense mutations.

Eur J Med Chem 2020 Aug 21;200:112436. Epub 2020 May 21.

Department of Medicine, University of Alabama at Birmingham (UAB), USA; Department of Pediatrics, University of Alabama at Birmingham (UAB), USA; Department of Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), USA. Electronic address:

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is unlikely that any one approach will be efficient in correcting all defects. The recent approvals of ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor represent the genesis of a new era of precision combination medicine for the CF patient population. In this review, we discuss targeted translational readthrough approaches as mono and combination therapies for CFTR nonsense mutations. We examine the current status of efficacy of translational readthrough/nonsense suppression therapies and their limitations, including non-native amino acid incorporation at PTCs and nonsense-mediated mRNA decay (NMD), along with approaches to tackle these limitations. We further elaborate on combining various therapies such as readthrough agents, NMD inhibitors, and corrector/potentiators to improve the efficacy and safety of suppression therapy. These mutation specific strategies that are directed towards the basic CF defects should positively impact CF patients bearing nonsense mutations.
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http://dx.doi.org/10.1016/j.ejmech.2020.112436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384597PMC
August 2020

Human Nasal Epithelial Organoids for Therapeutic Development in Cystic Fibrosis.

Genes (Basel) 2020 05 29;11(6). Epub 2020 May 29.

Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL 35294, USA.

We describe a human nasal epithelial (HNE) organoid model derived directly from patient samples that is well-differentiated and recapitulates the airway epithelium, including the expression of cilia, mucins, tight junctions, the cystic fibrosis transmembrane conductance regulator (CFTR), and ionocytes. This model requires few cells compared to airway epithelial monolayer cultures, with multiple outcome measurements depending on the application. A novel feature of the model is the predictive capacity of lumen formation, a marker of baseline CFTR function that correlates with short-circuit current activation of CFTR in monolayers and discriminates the cystic fibrosis (CF) phenotype from non-CF. Our HNE organoid model is amenable to automated measurements of forskolin-induced swelling (FIS), which distinguishes levels of CFTR activity. While the apical side is not easily accessible, RNA- and DNA-based therapies intended for systemic administration could be evaluated in vitro, or it could be used as an ex vivo biomarker of successful repair of a mutant gene. In conclusion, this highly differentiated airway epithelial model could serve as a surrogate biomarker to assess correction of the mutant gene in CF or other diseases, recapitulating the phenotypic and genotypic diversity of the population.
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http://dx.doi.org/10.3390/genes11060603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349680PMC
May 2020

Novel Therapy of Bicarbonate, Glutathione, and Ascorbic Acid Improves Cystic Fibrosis Mucus Transport.

Am J Respir Cell Mol Biol 2020 09;63(3):362-373

Cystic Fibrosis Research Center.

Defective airway mucus clearance is a defining characteristic of cystic fibrosis lung disease, and improvements to current mucolytic strategies are needed. Novel approaches targeting a range of contributing mechanisms are in various stages of preclinical and clinical development. ARINA-1 is a new nebulized product comprised of ascorbic acid, glutathione, and bicarbonate. Using microoptical coherence tomography, we tested the effect of ARINA-1 on central features of mucociliary clearance in F508del/F508del primary human bronchial epithelial cells to assess its potential as a mucoactive therapy in cystic fibrosis. We found that ARINA-1 significantly augmented mucociliary transport rates, both alone and with CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy, whereas airway hydration and ciliary beating were largely unchanged compared with PBS vehicle control. Analysis of mucus reflectivity and particle-tracking microrheology indicated that ARINA-1 restores mucus clearance by principally reducing mucus layer viscosity. The combination of bicarbonate and glutathione elicited increases in mucociliary transport rate comparable to those seen with ARINA-1, indicating the importance of this interaction to the impact of ARINA-1 on mucus transport; this effect was not recapitulated with bicarbonate alone or bicarbonate combined with ascorbic acid. Assessment of CFTR chloride transport revealed an increase in CFTR-mediated chloride secretion in response to ARINA-1 in CFBE41o cells expressing wild-type CFTR, driven by CFTR activity stimulation by ascorbate. This response was absent in CFBE41o F508del cells treated with VX-809 and primary human bronchial epithelial cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on cystic fibrosis mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in cystic fibrosis.
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http://dx.doi.org/10.1165/rcmb.2019-0287OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462336PMC
September 2020

Ataluren/ivacaftor combination therapy: Two N-of-1 trials in cystic fibrosis patients with nonsense mutations.

Pediatr Pulmonol 2020 07 13;55(7):1838-1842. Epub 2020 Apr 13.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) produce nonfunctional protein. No approved therapies exist for PTC mutations, including W1282X. We hypothesized that ivacaftor, combined with readthrough therapy, may benefit W1282X patients. Two N-of-1 clinical trials were conducted with ataluren and ivacaftor in various combinations. No meaningful clinical benefit was observed in either patient with ivacaftor alone or ataluren/ivacaftor combination. However, isolated improvements of uncertain significance were noted by a nasal potential difference (NPD) and FEV % with ivacaftor in Patient-1 and with ataluren/ivacaftor combination by NPD and body mass index in Patient-2. Drug regimen composed of readthrough agents and potentiators warrant further development for W1282X and other CFTR nonsense mutations.
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http://dx.doi.org/10.1002/ppul.24764DOI Listing
July 2020

Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?

Neurology 2020 03 26;94(11):481-494. Epub 2020 Feb 26.

From the Department of Neurology (A.J.E.), James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, OH; Edmond J. Safra Program in Parkinson's Disease (L.V.K.), Krembil Research Institute, Toronto Western Hospital, Ontario, Canada; Department of Neurology and Neurosurgery (Z.G.-O.), Montreal Neurological Institute, and Department of Human Genetics (Z.G.-O.), McGill University, Montreal, Quebec, Canada; Department of Clinical Neurosciences (C.H.W.-G.), John van Geest Centre for Brain Repair, University of Cambridge, UK; Division of Medical Oncology and Hematology (P.L.B.), Princess Margaret Cancer Centre, University Health Network, and Department of Medicine (P.L.B.), University of Toronto, Ontario, Canada; Departments of Medicine (S.M.R.), Pediatrics (S.M.R.), Cell Developmental and Integrative Biology (S.M.R.), and Neurology (D.G.S.), University of Alabama at Birmingham; Department of Clinical and Experimental Medicine (F.M.), University of Messina, Italy; Institute of Molecular and Clinical Sciences (F.M.), St George's University of London, UK; Edmond J. Safra Program in Parkinson's Disease (A.F., A.P.S., A.E.L.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto; Krembil Research Institute (A.F., A.P.S., A.E.L.); Tomorrow Edition (B.S.), Toronto, Ontario, Canada; Consultorio y Laboratorio de Neurogenética (M.A.K.), Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA; Programa de Medicina de Precision y Genomica Clinica (M.A.K.), Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Buenos Aires, Argentina; Clinical Genomics Program (M.J.F.), Norman Fixel Institute for Neurological Diseases, McKnight Brain Institute, University of Florida Clinical and Translational Science Institute, Gainesville; Clinical Trials Statistical & Data Management Center (C.S.C.), University of Iowa College of Public Health, Iowa City; Department of Neurology (M.A.S.), Massachusetts General Hospital, Boston; Michael J. Fox Foundation for Parkinson's Research (T.S.), New York City, NY; Department of Neurology (R.B.P.), Montreal General Hospital, Quebec; Research Imaging Centre (A.P.S.), Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada; Laboratory of Neurogenetics (A.B.S.), National Institute on Aging, NIH, Bethesda, MD; Department of Clinical Neurosciences (R.A.B.), John van Geest Centre for Brain Repair, WT-MRC Cambridge Stem Cell Institute, University of Cambridge, UK; Clinical Trials Coordination Center (K.K.), University of Rochester Medical Center, NY; Department of Neurology and Neuroscience (C.W.O.), Mount Sinai School of Medicine, New York, NY; Clintrex LLC (C.W.O.), Sarasota, FL; Division of Neurosurgery (A.L.), Krembil Neuroscience Institute, Toronto Western Hospital, Ontario, Canada; Department of Neurological Sciences (J.H.K.), Rush University Medical Center, Chicago, IL; Coeruleus Clinical Sciences (J.M.C.), Woodbridge, CT; and Center for Neurodegenerative Science (P.B.), Van Andel Institute, Grand Rapids, MI.

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.
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http://dx.doi.org/10.1212/WNL.0000000000009107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220234PMC
March 2020

Tobacco smoke exposure and socioeconomic factors are independent predictors of pulmonary decline in pediatric cystic fibrosis.

J Cyst Fibros 2020 09 17;19(5):783-790. Epub 2020 Feb 17.

The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Background: Pulmonary decline in CF is heterogeneous, with socio-environmental factors contributing to this variability. Few studies have attempted to disentangle the effects of tobacco smoke exposure and socioeconomic factors on lung function deterioration in pediatric CF. The current study evaluates their contributions longitudinally across the entire U.S. CF care network population.

Methods: Data from the CF Foundation Patient Registry were obtained on all individuals who at the end of 2016 were 6-18 years old. Lung function measures (ppFEV) for each person were calculated at each attained age. Multivariable analyses used mixed modeling to assess the impact of smoke exposure and socioeconomic factors on initial lung function and change over time.

Results: The sample included 10,895 individuals contributing 65,581 person years. At age 6, ppFEV of smoke-exposed children was 4.7% lower than among unexposed. The deficit persisted through age 18. In adjusted mixed models, smoke exposure and socioeconomic factors had independent, additive associations with lung function. Median ppFEV declined 2.4% with smoke exposure, 4.9% with lower paternal education, 0.3% with public insurance, and increased 0.2% with each $10,000 annual household income. The effect of smoke exposure on ppFEV was larger in disadvantaged children compared to privileged counterparts (3.2% vs 1.2%).

Conclusions: Smoke exposure and socioeconomic factors are independent risk factors for decreased ppFEV in pediatric CF. Smoking cessation strategies should be emphasized at the time of CF diagnosis and reiterated during infancy and early childhood. Interventions may be prioritized in disadvantaged families, where the exposure has a disproportionately large effect.
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http://dx.doi.org/10.1016/j.jcf.2020.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429279PMC
September 2020