Inhalation of Moli1901 in Patients With Cystic Fibrosis

Grasemann, Hartmut; Stehling, Florian; Brunar, Helmut; Widmann, Rudolf; Laliberte, T.W.; Molina, Luís; Döring, Gerd; Ratjen, Félix

doi:10.1378/chest.06-2085

Cited by 118 publications

(68 citation statements)

References 14 publications

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“…In phase 2 European trials, Moli1901 was well tolerated in most patients (one participant experienced a transient decrease in pulmonary function). Those receiving treatment of 2.5 mg daily of inhaled Moli1901 showed significant improvement in lung function measured as forced expiratory volume in one second (FEV 1 ; Grasemann et al, 2007).Initially promising, Denufosol, a P2Y2 agonist developed by Inspire, was believed to rehydrate the airway surface liquid, bypassing the basic CFTR protein defect, producing improvement in pulmonary function (Kellerman et al, 2008). However, the most recent clinical trial found it to be without effect.…”

Section: Mucolytics/airway-rehydrating Agentsmentioning

confidence: 99%

Channel Replacement Therapy for Cystic Fibrosis

Tomich¹,

Bukovnik²,

Layman³

et al. 2012

Cystic Fibrosis - Renewed Hopes Through Research

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Section: Mucolytics/airway-rehydrating Agentsmentioning

confidence: 99%

Channel Replacement Therapy for Cystic Fibrosis

Tomich¹,

Bukovnik²,

Layman³

et al. 2012

Cystic Fibrosis - Renewed Hopes Through Research

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“…Additionally, activation of the P2Y2 receptor on type II alveolar cells induces release of surfactant, which helps to maintain the integrity of the small airways. Another drug, Moli1901, works by increasing the activity of non-CFTR chloride channels, and there is evidence of clinical efficacy for these compounds [96]. Inhalation of hypertonic saline preceded by a bronchodilator [97,98] has recently been shown to improve lung function in CF patients with varying severities of lung disease, and as a result, there are now studies underway looking at the efficacy of hypertonic saline in infants with CF.…”

Section: Targeting the Consequences Of Defective Cftr Functionmentioning

confidence: 99%

“…Clinical trials ongoing, three drugs in phase I to II studies, others in pre-clinical development [62,94,96]. Limited success to date with use of aminoglycoside drugs to suppress stop mutations [82,83] Strategies that target the consequences of defective CFTR function…”

Section: Strategymentioning

confidence: 99%

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

100

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Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

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“…Although actinomycetes have not generally been recognized as prolific producers of potentially useful lantibiotics, two actinomycete compounds, NVB302 [an actagardine derivative (9)] and NAI-107 [also known as microbisporicin (10)] are currently in clinical development as anti-infectives, whereas a third, Moli1901 (also known as lancovutide or duramycin, a structural analog of cinnamycin), promises to be a useful adjunct for the treatment of cystic fibrosis (11,12). Actinomycete RiPPs that have been analyzed genetically include cinnamycin (13), the spore-associated proteins SapB (14) and SapT (15), michiganin (16), actagardine (17), deoxyactagardine (18), microbisporicin (19,20), cypemycin (21), venezuelin (22), and grisemycin (23).…”

mentioning

confidence: 99%

The antibiotic planosporicin coordinates its own production in the actinomycete Planomonospora alba

Sherwood

Bibb

2013

Proc. Natl. Acad. Sci. U.S.A.

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Planosporicin is a ribosomally synthesized, posttranslationally modified peptide lantibiotic produced by the actinomycete Planomonospora alba. It contains one methyl-lanthionine and four lanthionine bridges and inhibits cell wall biosynthesis in other Gram-positive bacteria probably by binding to lipid II, the immediate precursor for cell wall biosynthesis. Planosporicin production, which is encoded by a cluster of 15 genes, is confined to stationary phase in liquid culture and to the onset of morphological differentiation when P. alba is grown on agar. This growth phase-dependent gene expression is controlled transcriptionally by three pathway-specific regulatory proteins: an extracytoplasmic function σ factor (PspX), its cognate anti-σ factor (PspW), and a transcriptional activator (PspR) with a C-terminal helix-turn-helix DNA-binding domain. Using mutational analysis, S1 nuclease mapping, quantitative RT-PCR, and transcriptional fusions, we have determined the direct regulatory dependencies within the planosporicin gene cluster and present a model in which subinhibitory concentrations of the lantibiotic function in a feed-forward mechanism to elicit high levels of planosporicin production. We show that in addition to acting as an antibiotic, planosporicin can function as an extracellular signaling molecule to elicit precocious production of the lantibiotic, presumably ensuring synchronous and concerted lantibiotic biosynthesis in the wider population and, thus, the production of ecologically effective concentrations of the antibiotic.

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Inhalation of Moli1901 in Patients With Cystic Fibrosis

Cited by 118 publications

References 14 publications

Channel Replacement Therapy for Cystic Fibrosis

Channel Replacement Therapy for Cystic Fibrosis

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

The antibiotic planosporicin coordinates its own production in the actinomycete Planomonospora alba

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