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

Adewale, Adegboyega Timothy; Libby, Emily Falk; Fu, Lianwu; Lenzie, Andrew; Boitet, Evan R; Birket, Susan E.; Petty, Courtney Fernandez; Johns, J. Dixon; Mazur, Marina; Tearney, Guillermo J.; Copeland, Dan; Durham, Carolyn; Rowe, Steven M.

doi:10.1165/rcmb.2019-0287oc

Cited by 12 publications

(27 citation statements)

References 48 publications

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“…For these individuals, multi-modal therapies are anticipated to be most effective [28,46,77]. This laboratory study suggests that muco-active agents [4,18,36,55,77] which possess elements which address both the DNA and the mucous glycoproteins, in all their complex forms and interactions, would potentially improve airway clearance for the widest population of individuals with CF, and considering the heterogeneity of CF mucus, in time and space, may potentially prove useful at all stages of exacerbation, infection, inflammation, and obstruction.…”

Section: Cf Mucus Content As Potential Guide To Enhanced Airway Therapeutics Interventionsmentioning

confidence: 88%

“…CF sputum is known to have unique physical properties, including increased adhesivity, tenacity, and altered viscoelastic rheology, marked dehydration, and diminished transportability [1,4,12,13,17,18,32,37,38,[40][41][42]46,50,52,55,56,75]. It has also been said that CF sputum gets it CF character from its purulency [14].…”

Section: Cf Sputa Visual and Compositional Characteristicsmentioning

confidence: 99%

“…With a wide variety of therapeutic interventions, developed over many decades, quality of life and longevity of individuals with CF have dramatically improved [5,6,[34][35][36]43,96,97]. It remains paramount, however, to address the issues of chronic obstruction, inflammation, and infection in CF, with the development of additional novel mucolytic, anti-inflammatory, and anti-infective strategies and agents, especially for those individuals with advanced lung disease and those for whom current pharmacological agents are not effective or accessible [3][4][5]18,28,[31][32][33][34]46,47,55,77,91]. Our ex vivo hands-on observations predict that continued improvements in therapeutic options for the chronic obstruction, infection, and inflammation in CF and COPDs will address in vivo CF mucus as a dynamic conglomerate.…”

Section: Cf Mucus Content As Potential Guide To Enhanced Airway Therapeutics Interventionsmentioning

confidence: 99%

“…These data suggest that for airway specimens where one component dominates, addressing that component would be predicted to be beneficial to reduce aberrant mucus characteristics and improve MCC. Such strategies would include, for sputa with high DNA content, targeting DNA degradation [31,37,38,45,77], and for sputa with high mucous glycoprotein content, addressing the mucin polymer interactions and providing more hydration [4,17,18,31,32,46,49,55,77,83]. CF sputa solubilization in the lab was more readily achieved when the combined mucous glycoprotein and DNA content was less than 10% MDW, suggesting that therapeutics to reduce infection and inflammation may also assist in lowering GP and DNA levels, potentially lowering total solids, and thereby improving osmotic conditions and MCC.…”

Section: Cf Mucus Content As Potential Guide To Enhanced Airway Therapeutics Interventionsmentioning

confidence: 99%

“…CF mucus is more adherent, viscous, dehydrated, and impairs normal mucociliary escalator clearance [1,4,9,10,16,17,28,30,32,40,42,[49][50][51]. Alterations in, and macromolecular complexity of, CF secretions create physical and chemical barriers to the immune system, to regional ventilation, to antibiotic and mucolytic agents, and to potential gene therapy vehicles [4,37,48,50,[52][53][54][55][56]. CF mucus is a rich mixture of plasma proteins, inflammatory cells, DNA, bacteria, and bacterial products, with alveolar and tracheobronchial epithelial and submucosal gland secretions.…”

Section: Introductionmentioning

confidence: 99%

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Observations of, and Insights into, Cystic Fibrosis Mucus Heterogeneity in the Pre-Modulator Era: Sputum Characteristics, DNA and Glycoprotein Content, and Solubilization Time

Chance

Mawhinney

2020

JoR

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Airway obstruction with chronic inflammation and infection are major contributors to the lung damage and mortality of cystic fibrosis (CF). A better understanding of the congested milieu of CF airways will aid in improving therapeutic strategies. This article retrospectively reports our observations, and discusses insights gained in the handling and analysis of CF sputa. CF and non-CF mucus samples were surveyed for morphological features by electron microscopy and analyzed for the macromolecular dry weight (MDW), total protein, lipid, carbohydrate, and DNA. Mucus character was investigated with chemical solubilization time as a comparative tool. CF mucus appeared distinctly thick, viscous, and heterogeneous, with neutrophils as the dominant immune cell. CF sputum DNA content varied markedly for and between individuals (~1–10% MDW), as did solubilization times (~1–20 h). CF Sputum DNA up to 7.1% MDW correlated positively with solubilization time, whereas DNA >7.1% MDW correlated negatively. 3D analysis of CF sputa DNA, GP, and solubilization times revealed a dynamic and predictive relationship. Reflecting on the heterogeneous content and character of CF mucus, and the possible interplay in space and time in the respiratory tract of polymeric DNA and mucous glycoproteins, we highlight it’s potential to affect infection-related airway pathologies and the success of therapeutic interventions.

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Section: Cf Mucus Content As Potential Guide To Enhanced Airway Therapeutics Interventionsmentioning

confidence: 88%

Section: Cf Sputa Visual and Compositional Characteristicsmentioning

confidence: 99%

Section: Cf Mucus Content As Potential Guide To Enhanced Airway Therapeutics Interventionsmentioning

confidence: 99%

Section: Cf Mucus Content As Potential Guide To Enhanced Airway Therapeutics Interventionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Observations of, and Insights into, Cystic Fibrosis Mucus Heterogeneity in the Pre-Modulator Era: Sputum Characteristics, DNA and Glycoprotein Content, and Solubilization Time

Chance

Mawhinney

2020

JoR

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Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia

Cho,

Rivers,

Lim

et al. 2023

Int Forum Allergy Rhinol

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IntroductionCystic fibrosis (CF) airway disease is characterized by thick mucus and impaired mucociliary transport (MCT). Loss of functional cystic fibrosis transmembrane receptor (CFTR) leads to acidification and oxidation of airway surface mucus. Replacing bicarbonate (HCO3−) topically fails due to rapid reabsorption and neutralization, while the scavenging antioxidant, glutathione sulfhydryl (GSH), is also rapidly degraded. The objective of this study is to investigate GSH/NaHCO3 nanoparticles as novel strategy for CF airway disease.MethodsGSH/NaHCO3 poly (lactic‐co‐glycolic acid) nanoparticles were tested on primary CF (F508del/F508del) epithelial cultures to evaluate dose‐release curves, surface pH, toxicity, and MCT indices using micro‐optical coherence tomography. In vivo tests were performed in three rabbits to assess safety and toxicity. After 1 week of daily injections, histopathology, computed tomography (CT), and blood chemistries were performed and compared to three controls. Fluorescent nanoparticles were injected into a rabbit with maxillary sinusitis and explants visualized with confocal microscopy.ResultsSustained release of GSH and HCO3− with no cellular toxicity was observed over 2 weeks. Apical surface pH gradually increased from 6.54 ± 0.13 (baseline) to 7.07 ± 0.10 (24 h) (p < 0.001) and 6.87 ± 0.05 at 14 days (p < 0.001). MCT, ciliary beat frequency, and periciliary liquid were significantly increased. When injected into the maxillary sinuses of rabbits, there were no changes to histology, CT, or blood chemistries. Nanoparticles penetrated rabbit sinusitis mucus on confocal microscopy.ConclusionFindings suggest that GSH/NaHCO3− nanoparticles are a promising treatment option for viscous mucus in CF and other respiratory diseases of mucus obstruction such as chronic rhinosinusitis.

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Extracellular vesicles enhance pulmonary transduction of stably associated adeno‐associated virus following intratracheal administration

Kwak

Gololobova

Sharma

et al. 2023

J of Extracellular Vesicle

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Adeno‐associated virus (AAV) vector has shown multiple clinical breakthroughs, but its clinical implementation in inhaled gene therapy remains elusive due to difficulty in transducing lung airway cells. We demonstrate here AAV serotype 6 (AAV6) associated with extracellular vesicles (EVs) and secreted from vector‐producing HEK‐293 cells during vector preparation (EVAAV6) as a safe and highly efficacious gene delivery platform for inhaled gene therapy applications. Specifically, we discovered that EVAAV6 provided markedly enhanced reporter transgene expression in mucus‐covered air‐liquid interface (ALI) cultures of primary human bronchial and nasal epithelial cells as well as in mouse lung airways compared to standard preparations of AAV6 alone. Of note, AAV6 has been previously shown to outperform other clinically tested AAV serotypes, including those approved by the FDA for treating non‐lung diseases, in transducing ALI cultures of primary human airway cells. We provide compelling experimental evidence that the superior performance of EVAAV6 is attributed to the ability of EV to facilitate mucus penetration and cellular entry/transduction of AAV6. The tight and stable linkage between AAV6 and EVs appears essential to exploit the benefits of EVs given that a physical mixture of individually prepared EVs and AAV6 failed to mediate EV‐AAV6 interactions or to enhance gene transfer efficacy.

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

Cited by 12 publications

References 48 publications

Observations of, and Insights into, Cystic Fibrosis Mucus Heterogeneity in the Pre-Modulator Era: Sputum Characteristics, DNA and Glycoprotein Content, and Solubilization Time

Observations of, and Insights into, Cystic Fibrosis Mucus Heterogeneity in the Pre-Modulator Era: Sputum Characteristics, DNA and Glycoprotein Content, and Solubilization Time

Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia

Extracellular vesicles enhance pulmonary transduction of stably associated adeno‐associated virus following intratracheal administration

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