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Just uttering the word “mucus” is often sufficient to elicit amusement from those within earshot, but to patients with chronic inflammatory airway diseases, mucus is no laughing matter.
, which are then moved by cilia out of the airways for expulsion through coughing.
But in cystic fibrosis (CF), for example, mucus hypersecretion can be deadly. The underlying pathology of CF – a mutation in the CFTR gene, which codes for the protein CF transmembrane conductance regulator – leads to buildup in the lungs of abnormally viscous and sticky mucus, resulting in frequent, severe infections (particularly with Pseudomonas aeruginosa), progressive lung damage, and prior to the development of effective disease management, significantly premature death.
Mucus hypersecretion is also a feature of chronic obstructive pulmonary disease (COPD), noted Victor Kim, MD, from Temple University, Philadelphia, Christopher M. Evans, PhD, from the University of Colorado at Denver, Aurora, and Burton F. Dickey, MD, from the University of Texas MD Anderson Cancer Center, Houston.
In COPD, “mucus dysfunction arises from several mechanisms, including excess production due to inflammation, decreased elimination due to impaired ciliary clearance and reduced cough efficiency, and excessive concentration due to smoke-induced dysfunction of transepithelial anion transport resembling CF,” they wrote in an editorial published in the American Journal of Respiratory and Critical Care Medicine.
In patients with idiopathic pulmonary fibrosis, a polymorphism in the enhancer region of MUC5B, a gene that encodes for mucin glycoproteins, results in a 20-fold overexpression of the gene and prominent mucus production that has been shown to parallel lung inflammation and decline in forced vital capacity (FVC).
In patients with asthma, up-regulation of MUC5AC and stimulated mucus secretion conspire to obstruct airways, which can in extreme cases lead to death.
‘Short shrift’
Yet until recently, the role of mucus hypersecretion in diseases such as COPD has been largely overlooked, or as Dr. Kim and colleagues put it, “airway mucus often receives short shrift from clinicians.”
“It’s a pretty hot topic in pulmonary medicine today because it has been so neglected for so long,” Dr. Dickey said in an interview with CHEST Physician. “As clinicians we haven’t had a way to identify who needs treatment, which is ridiculous, because many of the people who expectorate a lot, like those with chronic bronchitis, don’t actually have small airway obstruction, and conversely, a lot of asthmatics, who have very serious small airway obstruction, don’t expectorate, so you can’t really tell from symptoms.”
What has changed in recent years is the use of chest CT to image muco-obstructive pathology, commonly called “mucus plugging” in the peripheral airways of patients with COPD and asthma.
“In the last decade or so, we’ve seen the emergence in obstructive lung diseases such as asthma and COPD the use of more objective measures on CT scans, including the problem of mucus plugging, which is unfortunately very common,” Dr. Kim said in an interview.
The discovery of the extent and severity of mucus in obstructive lung diseases has led to new strategies to combat mucus overconcentration, such as hydration, mucolytics, and an intriguing investigational approach to decrease calcium-induced hypersecretion with designer peptides.
Mighty mucins
Under normal physiologic conditions mucus is composed largely of water (97%) and salts (2%), with the remainder consisting of entrapped globular proteins (0.7%) and mucins (0.3%), Dr. Dickey explains.
Yet those meager mucins pack a real punch, with the ability to absorb 300 times their mass of water after secretion, creating mucus of optimal consistency and viscoelasticity.
“Personally, I’ve never understood – maybe I should have paid more attention in physics – how a compound can absorb 300-fold its mass, but it does,” he said.
In a recent review article in the journal Clinical and Translational Medicine, Dr. Dickey and colleagues described how good mucus can go bad.
“[H]igh levels of mucin production from inflammatory stimulation (termed ‘mucous metaplasia’), followed by rapid release (together, termed ‘mucus hypersecretion’), can plug airways due to mucus volume expansion. In addition, if available lumenal liquid is insufficient, concentrated mucus of excessive viscoelasticity and adhesivity can cause mucus stasis,” they wrote.
Therapeutic strategies
In patients with CF, CFTR modulator therapy has markedly reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. The manipulations can include both manual percussion and the use of devices for high-frequency chest wall oscillation.
Unlike in CF, where treating the underlying genetic pathology can help to resolve the thick, sticky mucus problems and thereby significantly reduce risk of infections and progressive lung damage, treatment of mucus metaplasia or hypersecretion in other diseases is aimed at symptomatic relief; it is still unclear whether symptomatic improvement of mucus overproduction would correlate with other disease-related outcomes, Dr. Kim and Dr. Dickey noted.
Potential therapeutic strategies to reduce excess mucus in the lungs include the use of mucolytic agents to thin secretions for more effective expulsion, decreasing mucus production through the use of an interleukin-13 (IL-13) inhibitor such as the anti-asthma agent dupilumab (Dupixent), and a novel strategy, still in the experimental phase, aimed at “disrupting the fusion of mucin storage granules with the cell membrane, thereby blocking secretion,” wrote Irina Gitlin, PhD, and John Fahy, MD, from the University of California, San Francisco, in Nature.
They were referring to research by Dr. Dickey and colleagues described in the same issue of Nature focusing on the inhibition of calcium-triggered mucus secretion by the use of hydrocarbon-stapled peptides, short chains of amino acids stabilized with a chemical bridge to a hydrocarbon molecule.
Knocking secretion down, but not out
The work has centered on decreasing overproduction of mucins with a focus on the signals for mucin production, including IL-13 and interleukin-1 beta, and on the signals for rapid release of mucins, including adenosine 5’-triphosphate (ATP), best known as an intracellular energy-storage module.
“But ATP is also steadily released by ciliated cells in response to the shear stress of tidal breathing, and it tells the neighboring secretory cells to slowly and steadily release mucin. But if the ciliated cells get stressed by any of a number of mechanisms, it can release a lot of ATP, and then the secretory cell can explosively release essentially all of its mucin content,” Dr. Dickey explained.
Other important signals for rapid release of mucins are acetylcholine and histamine, and all three of these agonists – ATP, acetylcholine, and histamine – cause a rise in intracellular calcium, which triggers calcium sensors that then lead to calcium-triggered membrane fusion and secretion.
Working as a postdoc in the Dickey laboratory, Dr. Evans had previously shown that deleting MUC5B in mice led to early development of serious lung abnormalities, some of which were fatal, indicating that MUC5B, a gene that is highly preserved in evolution, is essential for respiratory health.
This observation was later supported by a study of a family with a pattern of hereditary mucin deficiency caused by a homozygous loss-of-function mutation in MUC5B. The main subject in this study was an adult woman with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infections. Her sibling, who also had the biallelic mutation, had extensive sinus disease with nasal polyps. Other siblings who were heterozygous for the mutation were asymptomatic but had mild functional lung impairment.
The trick for the investigators, then, was to figure out how to reduce stimulated release of stored mucins while still preserving normal release of mucins to allow for ciliary clearance of mucus, and Dr. Dickey and colleagues appear to have accomplished this, at least in mice.
They first validated as a potential therapeutic target a protein labeled synaptotagmin-2 (Syt2). Syt2 is a calcium sensor that is an essential part of the system that triggers calcium-triggered secretion. In a model for allergic asthma, mice with Syt2 deleted from airway epithelia had marked reductions in both stimulated mucin secretion and in mucus occlusion in airway lumens, but remained otherwise healthy with normal lung function.
Working with structural biologist Axel Brunger, PhD, from Stanford (Calif.) University, Dr. Dickey and coinvestigators developed and validated a peptide that could specifically inhibit Syt2, and found that it mimicked the action of the Syt2 deletion, preventing mucus occlusion in the allergic asthma model without adversely effecting normal production.
Not ready for prime time
Dr. Dickey and colleagues are now working to translate the therapy into a form that can be used in humans, most likely as an aerosol that could be used for acute treatment of patients with mucus plugging from asthma and COPD, and also as a therapy for patients with chronic disease.
“In the chronic situation, what we would hope to do is identify patients with muco-obstructive lung disease – asthma, COPD, cystic fibrosis – who have airway mucus obstruction and then use the inhaled peptide on a regular basis as one part of a program to try to prevent this chronic mucus occlusion,” Dr. Dickey said.
As Dr. Gitlin and Dr. Fahy wrote in their editorial, “by confirming that it is possible to block calcium-regulated mucin secretion, Lai and colleagues have shown the potential of such an approach as a new therapeutic strategy for lung illnesses associated with mucus pathology, including diseases such as asthma and COPD, for which there is a large unmet medical need.”
The study by Dr. Dickey and colleagues was supported by grants from the German Research Foundation, National Institutes of Health and the Cystic Fibrosis Foundation. Dr. Dickey disclosed consulting for Arrowhead Pharmaceuticals. Dr. Kim disclosed personal fees from Medscape and others. Dr. Evans reported no relevant disclosures. Dr. Fahy and Dr. Gitlin are named inventors on patents for mucolytic drugs, and shareholders in Aer Therapeutics.
Just uttering the word “mucus” is often sufficient to elicit amusement from those within earshot, but to patients with chronic inflammatory airway diseases, mucus is no laughing matter.
, which are then moved by cilia out of the airways for expulsion through coughing.
But in cystic fibrosis (CF), for example, mucus hypersecretion can be deadly. The underlying pathology of CF – a mutation in the CFTR gene, which codes for the protein CF transmembrane conductance regulator – leads to buildup in the lungs of abnormally viscous and sticky mucus, resulting in frequent, severe infections (particularly with Pseudomonas aeruginosa), progressive lung damage, and prior to the development of effective disease management, significantly premature death.
Mucus hypersecretion is also a feature of chronic obstructive pulmonary disease (COPD), noted Victor Kim, MD, from Temple University, Philadelphia, Christopher M. Evans, PhD, from the University of Colorado at Denver, Aurora, and Burton F. Dickey, MD, from the University of Texas MD Anderson Cancer Center, Houston.
In COPD, “mucus dysfunction arises from several mechanisms, including excess production due to inflammation, decreased elimination due to impaired ciliary clearance and reduced cough efficiency, and excessive concentration due to smoke-induced dysfunction of transepithelial anion transport resembling CF,” they wrote in an editorial published in the American Journal of Respiratory and Critical Care Medicine.
In patients with idiopathic pulmonary fibrosis, a polymorphism in the enhancer region of MUC5B, a gene that encodes for mucin glycoproteins, results in a 20-fold overexpression of the gene and prominent mucus production that has been shown to parallel lung inflammation and decline in forced vital capacity (FVC).
In patients with asthma, up-regulation of MUC5AC and stimulated mucus secretion conspire to obstruct airways, which can in extreme cases lead to death.
‘Short shrift’
Yet until recently, the role of mucus hypersecretion in diseases such as COPD has been largely overlooked, or as Dr. Kim and colleagues put it, “airway mucus often receives short shrift from clinicians.”
“It’s a pretty hot topic in pulmonary medicine today because it has been so neglected for so long,” Dr. Dickey said in an interview with CHEST Physician. “As clinicians we haven’t had a way to identify who needs treatment, which is ridiculous, because many of the people who expectorate a lot, like those with chronic bronchitis, don’t actually have small airway obstruction, and conversely, a lot of asthmatics, who have very serious small airway obstruction, don’t expectorate, so you can’t really tell from symptoms.”
What has changed in recent years is the use of chest CT to image muco-obstructive pathology, commonly called “mucus plugging” in the peripheral airways of patients with COPD and asthma.
“In the last decade or so, we’ve seen the emergence in obstructive lung diseases such as asthma and COPD the use of more objective measures on CT scans, including the problem of mucus plugging, which is unfortunately very common,” Dr. Kim said in an interview.
The discovery of the extent and severity of mucus in obstructive lung diseases has led to new strategies to combat mucus overconcentration, such as hydration, mucolytics, and an intriguing investigational approach to decrease calcium-induced hypersecretion with designer peptides.
Mighty mucins
Under normal physiologic conditions mucus is composed largely of water (97%) and salts (2%), with the remainder consisting of entrapped globular proteins (0.7%) and mucins (0.3%), Dr. Dickey explains.
Yet those meager mucins pack a real punch, with the ability to absorb 300 times their mass of water after secretion, creating mucus of optimal consistency and viscoelasticity.
“Personally, I’ve never understood – maybe I should have paid more attention in physics – how a compound can absorb 300-fold its mass, but it does,” he said.
In a recent review article in the journal Clinical and Translational Medicine, Dr. Dickey and colleagues described how good mucus can go bad.
“[H]igh levels of mucin production from inflammatory stimulation (termed ‘mucous metaplasia’), followed by rapid release (together, termed ‘mucus hypersecretion’), can plug airways due to mucus volume expansion. In addition, if available lumenal liquid is insufficient, concentrated mucus of excessive viscoelasticity and adhesivity can cause mucus stasis,” they wrote.
Therapeutic strategies
In patients with CF, CFTR modulator therapy has markedly reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. The manipulations can include both manual percussion and the use of devices for high-frequency chest wall oscillation.
Unlike in CF, where treating the underlying genetic pathology can help to resolve the thick, sticky mucus problems and thereby significantly reduce risk of infections and progressive lung damage, treatment of mucus metaplasia or hypersecretion in other diseases is aimed at symptomatic relief; it is still unclear whether symptomatic improvement of mucus overproduction would correlate with other disease-related outcomes, Dr. Kim and Dr. Dickey noted.
Potential therapeutic strategies to reduce excess mucus in the lungs include the use of mucolytic agents to thin secretions for more effective expulsion, decreasing mucus production through the use of an interleukin-13 (IL-13) inhibitor such as the anti-asthma agent dupilumab (Dupixent), and a novel strategy, still in the experimental phase, aimed at “disrupting the fusion of mucin storage granules with the cell membrane, thereby blocking secretion,” wrote Irina Gitlin, PhD, and John Fahy, MD, from the University of California, San Francisco, in Nature.
They were referring to research by Dr. Dickey and colleagues described in the same issue of Nature focusing on the inhibition of calcium-triggered mucus secretion by the use of hydrocarbon-stapled peptides, short chains of amino acids stabilized with a chemical bridge to a hydrocarbon molecule.
Knocking secretion down, but not out
The work has centered on decreasing overproduction of mucins with a focus on the signals for mucin production, including IL-13 and interleukin-1 beta, and on the signals for rapid release of mucins, including adenosine 5’-triphosphate (ATP), best known as an intracellular energy-storage module.
“But ATP is also steadily released by ciliated cells in response to the shear stress of tidal breathing, and it tells the neighboring secretory cells to slowly and steadily release mucin. But if the ciliated cells get stressed by any of a number of mechanisms, it can release a lot of ATP, and then the secretory cell can explosively release essentially all of its mucin content,” Dr. Dickey explained.
Other important signals for rapid release of mucins are acetylcholine and histamine, and all three of these agonists – ATP, acetylcholine, and histamine – cause a rise in intracellular calcium, which triggers calcium sensors that then lead to calcium-triggered membrane fusion and secretion.
Working as a postdoc in the Dickey laboratory, Dr. Evans had previously shown that deleting MUC5B in mice led to early development of serious lung abnormalities, some of which were fatal, indicating that MUC5B, a gene that is highly preserved in evolution, is essential for respiratory health.
This observation was later supported by a study of a family with a pattern of hereditary mucin deficiency caused by a homozygous loss-of-function mutation in MUC5B. The main subject in this study was an adult woman with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infections. Her sibling, who also had the biallelic mutation, had extensive sinus disease with nasal polyps. Other siblings who were heterozygous for the mutation were asymptomatic but had mild functional lung impairment.
The trick for the investigators, then, was to figure out how to reduce stimulated release of stored mucins while still preserving normal release of mucins to allow for ciliary clearance of mucus, and Dr. Dickey and colleagues appear to have accomplished this, at least in mice.
They first validated as a potential therapeutic target a protein labeled synaptotagmin-2 (Syt2). Syt2 is a calcium sensor that is an essential part of the system that triggers calcium-triggered secretion. In a model for allergic asthma, mice with Syt2 deleted from airway epithelia had marked reductions in both stimulated mucin secretion and in mucus occlusion in airway lumens, but remained otherwise healthy with normal lung function.
Working with structural biologist Axel Brunger, PhD, from Stanford (Calif.) University, Dr. Dickey and coinvestigators developed and validated a peptide that could specifically inhibit Syt2, and found that it mimicked the action of the Syt2 deletion, preventing mucus occlusion in the allergic asthma model without adversely effecting normal production.
Not ready for prime time
Dr. Dickey and colleagues are now working to translate the therapy into a form that can be used in humans, most likely as an aerosol that could be used for acute treatment of patients with mucus plugging from asthma and COPD, and also as a therapy for patients with chronic disease.
“In the chronic situation, what we would hope to do is identify patients with muco-obstructive lung disease – asthma, COPD, cystic fibrosis – who have airway mucus obstruction and then use the inhaled peptide on a regular basis as one part of a program to try to prevent this chronic mucus occlusion,” Dr. Dickey said.
As Dr. Gitlin and Dr. Fahy wrote in their editorial, “by confirming that it is possible to block calcium-regulated mucin secretion, Lai and colleagues have shown the potential of such an approach as a new therapeutic strategy for lung illnesses associated with mucus pathology, including diseases such as asthma and COPD, for which there is a large unmet medical need.”
The study by Dr. Dickey and colleagues was supported by grants from the German Research Foundation, National Institutes of Health and the Cystic Fibrosis Foundation. Dr. Dickey disclosed consulting for Arrowhead Pharmaceuticals. Dr. Kim disclosed personal fees from Medscape and others. Dr. Evans reported no relevant disclosures. Dr. Fahy and Dr. Gitlin are named inventors on patents for mucolytic drugs, and shareholders in Aer Therapeutics.
Just uttering the word “mucus” is often sufficient to elicit amusement from those within earshot, but to patients with chronic inflammatory airway diseases, mucus is no laughing matter.
, which are then moved by cilia out of the airways for expulsion through coughing.
But in cystic fibrosis (CF), for example, mucus hypersecretion can be deadly. The underlying pathology of CF – a mutation in the CFTR gene, which codes for the protein CF transmembrane conductance regulator – leads to buildup in the lungs of abnormally viscous and sticky mucus, resulting in frequent, severe infections (particularly with Pseudomonas aeruginosa), progressive lung damage, and prior to the development of effective disease management, significantly premature death.
Mucus hypersecretion is also a feature of chronic obstructive pulmonary disease (COPD), noted Victor Kim, MD, from Temple University, Philadelphia, Christopher M. Evans, PhD, from the University of Colorado at Denver, Aurora, and Burton F. Dickey, MD, from the University of Texas MD Anderson Cancer Center, Houston.
In COPD, “mucus dysfunction arises from several mechanisms, including excess production due to inflammation, decreased elimination due to impaired ciliary clearance and reduced cough efficiency, and excessive concentration due to smoke-induced dysfunction of transepithelial anion transport resembling CF,” they wrote in an editorial published in the American Journal of Respiratory and Critical Care Medicine.
In patients with idiopathic pulmonary fibrosis, a polymorphism in the enhancer region of MUC5B, a gene that encodes for mucin glycoproteins, results in a 20-fold overexpression of the gene and prominent mucus production that has been shown to parallel lung inflammation and decline in forced vital capacity (FVC).
In patients with asthma, up-regulation of MUC5AC and stimulated mucus secretion conspire to obstruct airways, which can in extreme cases lead to death.
‘Short shrift’
Yet until recently, the role of mucus hypersecretion in diseases such as COPD has been largely overlooked, or as Dr. Kim and colleagues put it, “airway mucus often receives short shrift from clinicians.”
“It’s a pretty hot topic in pulmonary medicine today because it has been so neglected for so long,” Dr. Dickey said in an interview with CHEST Physician. “As clinicians we haven’t had a way to identify who needs treatment, which is ridiculous, because many of the people who expectorate a lot, like those with chronic bronchitis, don’t actually have small airway obstruction, and conversely, a lot of asthmatics, who have very serious small airway obstruction, don’t expectorate, so you can’t really tell from symptoms.”
What has changed in recent years is the use of chest CT to image muco-obstructive pathology, commonly called “mucus plugging” in the peripheral airways of patients with COPD and asthma.
“In the last decade or so, we’ve seen the emergence in obstructive lung diseases such as asthma and COPD the use of more objective measures on CT scans, including the problem of mucus plugging, which is unfortunately very common,” Dr. Kim said in an interview.
The discovery of the extent and severity of mucus in obstructive lung diseases has led to new strategies to combat mucus overconcentration, such as hydration, mucolytics, and an intriguing investigational approach to decrease calcium-induced hypersecretion with designer peptides.
Mighty mucins
Under normal physiologic conditions mucus is composed largely of water (97%) and salts (2%), with the remainder consisting of entrapped globular proteins (0.7%) and mucins (0.3%), Dr. Dickey explains.
Yet those meager mucins pack a real punch, with the ability to absorb 300 times their mass of water after secretion, creating mucus of optimal consistency and viscoelasticity.
“Personally, I’ve never understood – maybe I should have paid more attention in physics – how a compound can absorb 300-fold its mass, but it does,” he said.
In a recent review article in the journal Clinical and Translational Medicine, Dr. Dickey and colleagues described how good mucus can go bad.
“[H]igh levels of mucin production from inflammatory stimulation (termed ‘mucous metaplasia’), followed by rapid release (together, termed ‘mucus hypersecretion’), can plug airways due to mucus volume expansion. In addition, if available lumenal liquid is insufficient, concentrated mucus of excessive viscoelasticity and adhesivity can cause mucus stasis,” they wrote.
Therapeutic strategies
In patients with CF, CFTR modulator therapy has markedly reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. The manipulations can include both manual percussion and the use of devices for high-frequency chest wall oscillation.
Unlike in CF, where treating the underlying genetic pathology can help to resolve the thick, sticky mucus problems and thereby significantly reduce risk of infections and progressive lung damage, treatment of mucus metaplasia or hypersecretion in other diseases is aimed at symptomatic relief; it is still unclear whether symptomatic improvement of mucus overproduction would correlate with other disease-related outcomes, Dr. Kim and Dr. Dickey noted.
Potential therapeutic strategies to reduce excess mucus in the lungs include the use of mucolytic agents to thin secretions for more effective expulsion, decreasing mucus production through the use of an interleukin-13 (IL-13) inhibitor such as the anti-asthma agent dupilumab (Dupixent), and a novel strategy, still in the experimental phase, aimed at “disrupting the fusion of mucin storage granules with the cell membrane, thereby blocking secretion,” wrote Irina Gitlin, PhD, and John Fahy, MD, from the University of California, San Francisco, in Nature.
They were referring to research by Dr. Dickey and colleagues described in the same issue of Nature focusing on the inhibition of calcium-triggered mucus secretion by the use of hydrocarbon-stapled peptides, short chains of amino acids stabilized with a chemical bridge to a hydrocarbon molecule.
Knocking secretion down, but not out
The work has centered on decreasing overproduction of mucins with a focus on the signals for mucin production, including IL-13 and interleukin-1 beta, and on the signals for rapid release of mucins, including adenosine 5’-triphosphate (ATP), best known as an intracellular energy-storage module.
“But ATP is also steadily released by ciliated cells in response to the shear stress of tidal breathing, and it tells the neighboring secretory cells to slowly and steadily release mucin. But if the ciliated cells get stressed by any of a number of mechanisms, it can release a lot of ATP, and then the secretory cell can explosively release essentially all of its mucin content,” Dr. Dickey explained.
Other important signals for rapid release of mucins are acetylcholine and histamine, and all three of these agonists – ATP, acetylcholine, and histamine – cause a rise in intracellular calcium, which triggers calcium sensors that then lead to calcium-triggered membrane fusion and secretion.
Working as a postdoc in the Dickey laboratory, Dr. Evans had previously shown that deleting MUC5B in mice led to early development of serious lung abnormalities, some of which were fatal, indicating that MUC5B, a gene that is highly preserved in evolution, is essential for respiratory health.
This observation was later supported by a study of a family with a pattern of hereditary mucin deficiency caused by a homozygous loss-of-function mutation in MUC5B. The main subject in this study was an adult woman with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infections. Her sibling, who also had the biallelic mutation, had extensive sinus disease with nasal polyps. Other siblings who were heterozygous for the mutation were asymptomatic but had mild functional lung impairment.
The trick for the investigators, then, was to figure out how to reduce stimulated release of stored mucins while still preserving normal release of mucins to allow for ciliary clearance of mucus, and Dr. Dickey and colleagues appear to have accomplished this, at least in mice.
They first validated as a potential therapeutic target a protein labeled synaptotagmin-2 (Syt2). Syt2 is a calcium sensor that is an essential part of the system that triggers calcium-triggered secretion. In a model for allergic asthma, mice with Syt2 deleted from airway epithelia had marked reductions in both stimulated mucin secretion and in mucus occlusion in airway lumens, but remained otherwise healthy with normal lung function.
Working with structural biologist Axel Brunger, PhD, from Stanford (Calif.) University, Dr. Dickey and coinvestigators developed and validated a peptide that could specifically inhibit Syt2, and found that it mimicked the action of the Syt2 deletion, preventing mucus occlusion in the allergic asthma model without adversely effecting normal production.
Not ready for prime time
Dr. Dickey and colleagues are now working to translate the therapy into a form that can be used in humans, most likely as an aerosol that could be used for acute treatment of patients with mucus plugging from asthma and COPD, and also as a therapy for patients with chronic disease.
“In the chronic situation, what we would hope to do is identify patients with muco-obstructive lung disease – asthma, COPD, cystic fibrosis – who have airway mucus obstruction and then use the inhaled peptide on a regular basis as one part of a program to try to prevent this chronic mucus occlusion,” Dr. Dickey said.
As Dr. Gitlin and Dr. Fahy wrote in their editorial, “by confirming that it is possible to block calcium-regulated mucin secretion, Lai and colleagues have shown the potential of such an approach as a new therapeutic strategy for lung illnesses associated with mucus pathology, including diseases such as asthma and COPD, for which there is a large unmet medical need.”
The study by Dr. Dickey and colleagues was supported by grants from the German Research Foundation, National Institutes of Health and the Cystic Fibrosis Foundation. Dr. Dickey disclosed consulting for Arrowhead Pharmaceuticals. Dr. Kim disclosed personal fees from Medscape and others. Dr. Evans reported no relevant disclosures. Dr. Fahy and Dr. Gitlin are named inventors on patents for mucolytic drugs, and shareholders in Aer Therapeutics.