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Targeted Activation of Cystic Fibrosis Transmembrane Conductance Regulator: two molecular approaches to activate CFTR expression

https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(19)30314-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1525001619303144%3Fshowall%3Dtrue

https://www.ncbi.nlm.nih.gov/pubmed/31383454?dopt=Abstract

Related Articles

Targeted Activation of Cystic Fibrosis Transmembrane Conductance Regulator.

Mol Ther. 2019 Jul 15;:

Authors: Villamizar O, Waters SA, Scott T, Saayman S, Grepo N, Urak R, Davis A, Jaffe A, Morris KV

Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The majority of CFTR mutations result in impaired chloride channel function as only a fraction of the mutated CFTR reaches the plasma membrane. The development of a therapeutic approach that facilitates increased cell-surface expression of CFTR could prove clinically relevant. Here, we evaluate and contrast two molecular approaches to activate CFTR expression. We find that an RNA-guided nuclease null Cas9 (dCas9) fused with a tripartite activator, VP64-p65-Rta can activate endogenous CFTR in cultured human nasal epithelial cells from CF patients. We also find that targeting BGas, a long non-coding RNA involved in transcriptionally modulating CFTR expression with a gapmer, induced both strong knockdown of BGas and concordant activation of CFTR. Notably, the gapmer can be delivered to target cells when generated as electrostatic particles with recombinant HIV-Tat cell penetrating peptide (CPP), when packaged into exosomes, or when loaded into lipid nanoparticles (LNPs). Treatment of patient-derived human nasal epithelial cells containing F508del with gapmer-CPP, gapmer-exosomes, or LNPs resulted in increased expression and function of CFTR. Collectively, these observations suggest that CRISPR/dCas-VPR (CRISPR) and BGas-gapmer approaches can target and specifically activate CFTR.

PMID: 31383454 [PubMed – as supplied by publisher]

PubMed:31383454

Hinge-like protein may open new doors in cystic fibrosis treatment

https://www.sciencedaily.com/releases/2019/07/190709153612.htm

Hinge-like protein may open new doors in cystic fibrosis treatment

Date:
July 9, 2019

Source:
Rockefeller University

Summary:
Drugs known as potentiators alleviate some symptoms of cystic fibrosis. Researchers recently figured out how these compounds work–a finding that may lead to better drugs that patients can more easily afford.

Eluforsen improved CFTR function in cell and animal models of p.Phe508del-CFTR-mediated cystic fibrosis

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219182

https://www.ncbi.nlm.nih.gov/pubmed/31251792?dopt=Abstract

Related Articles

Evaluation of eluforsen, a novel RNA oligonucleotide for restoration of CFTR function in in vitro and murine models of p.Phe508del cystic fibrosis.

PLoS One. 2019;14(6):e0219182

Authors: Beumer W, Swildens J, Leal T, Noel S, Anthonijsz H, van der Horst G, Kuiperij-Boersma H, Potman M, van Putten C, Biasutto P, Platenburg G, de Jonge H, Henig N, Ritsema T

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene encoding the epithelial chloride channel CF transmembrane conductance regulator (CFTR) protein. The most common mutation is a deletion of three nucleotides leading to the loss of phenylalanine at position 508 (p.Phe508del) in the protein. This study evaluates eluforsen, a novel, single-stranded, 33-nucleotide antisense oligonucleotide designed to restore CFTR function, in in vitro and in vivo models of p.Phe508del CF. The aims of the study were to demonstrate cellular uptake of eluforsen, and its efficacy in functional restoration of p.Phe508del-CFTR both in vitro and in vivo. In vitro, the effect of eluforsen was investigated in human CF pancreatic adenocarcinoma cells and human bronchial epithelial cells. Two mouse models were used to evaluate eluforsen in vivo. In vitro, eluforsen improved chloride efflux in CF pancreatic adenocarcinoma cell cultures and increased short-circuit current in primary human bronchial epithelial cells, both indicating restoration of CFTR function. In vivo, eluforsen was taken up by airway epithelium following oro-tracheal administration in mice, resulting in systemic exposure of eluforsen. In female F508del-CFTR mice, eluforsen significantly increased CFTR-mediated saliva secretion (used as a measure of CFTR function, equivalent to the sweat test in humans). Similarly, intranasal administration of eluforsen significantly improved nasal potential difference (NPD), and therefore CFTR conductance, in two CF mouse models. These findings indicate that eluforsen improved CFTR function in cell and animal models of p.Phe508del-CFTR-mediated CF and supported further development of eluforsen in human clinical trials, where eluforsen has also been shown to improve CFTR activity as measured by NPD.

PMID: 31251792 [PubMed – in process]

PubMed:31251792

AzurRx BioPharma Announces Initiation of Phase 2 Clinical Study for MS1819-SD in combination with standard PERT for Cystic Fibrosis Patients with Severe Exocrine Pancreatic Insufficiency

https://www.globenewswire.com/news-release/2019/07/08/1879728/0/en/AzurRx-BioPharma-Announces-Initiation-of-Phase-2-Clinical-Study-for-MS1819-SD-in-combination-with-standard-PERT-for-Cystic-Fibrosis-Patients-with-Severe-Exocrine-Pancreatic-Insuffi.html

AzurRx BioPharma Announces Initiation of Phase 2 Clinical Study for MS1819-SD in combination with standard PERT for Cystic Fibrosis Patients with Severe Exocrine Pancreatic Insufficiency

Current trends and developments in the clinical translation of nanomedicine for lung diseases, including cystic fibrosis

https://thorax.bmj.com/content/early/2019/07/08/thoraxjnl-2019-213037

https://www.ncbi.nlm.nih.gov/pubmed/31285360?dopt=Abstract

Nanotechnology based therapeutics for lung disease.

Thorax. 2019 Jul 08;:

Authors: Doroudian M, MacLoughlin R, Poynton F, Prina-Mello A, Donnelly SC

Abstract

Nanomedicine is a multidisciplinary research field with an integration of traditional sciences such as chemistry, physics, biology and materials science. The application of nanomedicine for lung diseases as a relatively new area of interdisciplinary science has grown rapidly over the last 10 years. Promising research outcomes suggest that nanomedicine will revolutionise the practice of medicine, through the development of new approaches in therapeutic agent delivery, vaccine development and nanotechnology-based medical detections. Nano-based approaches in the diagnosis and treatment of lung diseases will, in the not too distant future, change the way we practise medicine. This review will focus on the current trends and developments in the clinical translation of nanomedicine for lung diseases, such as in the areas of lung cancer, cystic fibrosis, asthma, bacterial infections and COPD.

PMID: 31285360 [PubMed – as supplied by publisher]

PubMed:31285360

A Clinical Study to Investigate Safety, Tolerability and Distribution of CHF 6333 After One or After Repeated Inhalation in Patients With Cystic Fibrosis (CF)

https://clinicaltrials.gov/ct2/show/NCT04010799?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=06%2F24%2F2019&lupd_d=14

Conditions :   Cystic Fibrosis;   Non-Cystic Fibrosis Bronchiectasis

Interventions :   Drug: CHF 6333;   Drug: Placebo

Sponsor :   Chiesi Farmaceutici S.p.A.

Recruiting

A Clinical Study to Investigate Safety, Tolerability and Distribution of CHF 6333 After One or After Repeated Inhalation in Patients With Cystic Fibrosis (CF) and in Patients With Non Cystic Fibrosis (NCFB) Bronchiectasis

NCT04010799

Mon, 08 Jul 2019 12:00:00 EDT

Last Update Posted: 07/08/19 07:51AM

CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection

https://www.ncbi.nlm.nih.gov/pubmed/31270271?dopt=Abstract

Related Articles

CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection.

Sci Transl Med. 2019 Jul 03;11(499):

Authors: Riquelme SA, Lozano C, Moustafa AM, Liimatta K, Tomlinson KL, Britto C, Khanal S, Gill SK, Narechania A, Azcona-Gutiérrez JM, DiMango E, Saénz Y, Planet P, Prince A

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.

PMID: 31270271 [PubMed – in process]

PubMed:31270271

Enabling Synthesis of ABBV-2222, A CFTR Corrector for the Treatment of Cystic Fibrosis

https://pubs.acs.org/doi/10.1021/acs.orglett.9b02099

https://www.ncbi.nlm.nih.gov/pubmed/31259557?dopt=Abstract

Enabling Synthesis of ABBV-2222, A CFTR Corrector for the Treatment of Cystic Fibrosis.

Org Lett. 2019 Jul 01;:

Authors: Greszler SN, Shelat B, Voight EA

Abstract

An enabling preclinical synthetic route to cystic fibrosis candidate ABBV-2222 is described. Two stereoselective steps provide access to an aminochroman intermediate with excellent control, and a late-stage demethylation/difluoromethylation sequence provides efficient access to the target molecule.

PMID: 31259557 [PubMed – as supplied by publisher]

PubMed:31259557

The Emerging Role of Neutrophil Extracellular Traps in Respiratory Disease

https://www.ncbi.nlm.nih.gov/pubmed/31265835?dopt=Abstract

The Emerging Role of Neutrophil Extracellular Traps in Respiratory Disease.

Chest. 2019 Jun 29;:

Authors: Twaddell SH, Baines KJ, Grainge C, Gibson PG

Abstract

Neutrophil extracellular traps (NETs) are extrusions of intracellular DNA and attached granular material which enable bacterial killing. NETs are increasingly recognised for their role in the pathogenesis of respiratory disease. NETs are composed of a complex mix of intracellular derived material which neutrophils organise within the cytoplasm then expel in a non-directed manner in the vicinity of invading organisms. Combined, these trap and destroy multiple genera of microbes including bacteria, fungi, viruses and protozoans, limiting infection especially where phagocytosis is not possible. Initially NET formation was thought to be a terminal event for neutrophils, however it is now apparent that some neutrophils survive this process becoming anuclear and may drive ongoing tissue damage. NETs are now known to be directly cytotoxic to lung epithelium and endothelium and their excessive production is seen in pneumonia and acute lung injury as well as several chronic diseases, including COPD, asthma and cystic fibrosis. NETs also appear to play a role in both tumour defence and dissemination depending on the local microenvironment and the specific tumour subtype. It is becoming increasingly apparent that NET formation can be a positive or negative influence on multiple respiratory pathologies and that simply globally reducing or increasing NET formation is unlikely to be a therapeutic success. Rather, as our understanding grows, it is likely that targeted NET up or downregulation along with destruction or protection of already formed NETs may be become an additional point of intervention for respiratory physicians.

PMID: 31265835 [PubMed – as supplied by publisher]

PubMed:31265835

Evaluation of eluforsen, a novel RNA oligonucleotide for restoration of CFTR function in in vitro and murine models of p.Phe508del cystic fibrosis

https://www.ncbi.nlm.nih.gov/pubmed/31251792?dopt=Abstract

Related Articles

Evaluation of eluforsen, a novel RNA oligonucleotide for restoration of CFTR function in in vitro and murine models of p.Phe508del cystic fibrosis.

PLoS One. 2019;14(6):e0219182

Authors: Beumer W, Swildens J, Leal T, Noel S, Anthonijsz H, van der Horst G, Kuiperij-Boersma H, Potman M, van Putten C, Biasutto P, Platenburg G, de Jonge H, Henig N, Ritsema T

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene encoding the epithelial chloride channel CF transmembrane conductance regulator (CFTR) protein. The most common mutation is a deletion of three nucleotides leading to the loss of phenylalanine at position 508 (p.Phe508del) in the protein. This study evaluates eluforsen, a novel, single-stranded, 33-nucleotide antisense oligonucleotide designed to restore CFTR function, in in vitro and in vivo models of p.Phe508del CF. The aims of the study were to demonstrate cellular uptake of eluforsen, and its efficacy in functional restoration of p.Phe508del-CFTR both in vitro and in vivo. In vitro, the effect of eluforsen was investigated in human CF pancreatic adenocarcinoma cells and human bronchial epithelial cells. Two mouse models were used to evaluate eluforsen in vivo. In vitro, eluforsen improved chloride efflux in CF pancreatic adenocarcinoma cell cultures and increased short-circuit current in primary human bronchial epithelial cells, both indicating restoration of CFTR function. In vivo, eluforsen was taken up by airway epithelium following oro-tracheal administration in mice, resulting in systemic exposure of eluforsen. In female F508del-CFTR mice, eluforsen significantly increased CFTR-mediated saliva secretion (used as a measure of CFTR function, equivalent to the sweat test in humans). Similarly, intranasal administration of eluforsen significantly improved nasal potential difference (NPD), and therefore CFTR conductance, in two CF mouse models. These findings indicate that eluforsen improved CFTR function in cell and animal models of p.Phe508del-CFTR-mediated CF and supported further development of eluforsen in human clinical trials, where eluforsen has also been shown to improve CFTR activity as measured by NPD.

PMID: 31251792 [PubMed – in process]

PubMed:31251792

Emerging gene therapies for cystic fibrosis

https://www.tandfonline.com/doi/abs/10.1080/17476348.2019.1634547?journalCode=ierx20

https://www.ncbi.nlm.nih.gov/pubmed/31215818?dopt=Abstract

Emerging gene therapies for cystic fibrosis.

Expert Rev Respir Med. 2019 Jun 19;:

Authors: Miah KM, Hyde SC, Gill DR

Abstract

Introduction: Cystic fibrosis (CF) remains a life-threatening genetic disease, with few clinically effective treatment options. Gene therapy and gene editing strategies offer the potential for a one-time CF cure, irrespective of the CFTR mutation class. Areas covered: We review emerging gene therapies and gene delivery strategies for the treatment of CF particularly viral and non-viral approaches with potential to treat CF. Expert opinion: It was initially anticipated that the challenge of developing a gene therapy for CF lung disease would be met relatively easily. Following early proof-of-concept clinical studies, CF gene therapy has entered a new era with innovative vector designs, approaches to subvert the humoral immune system and increase gene delivery and gene correction efficiencies. Developments include integrating adenoviral vectors, rapamycin loaded nanoparticles and lung-tropic lentiviral vectors. The characterisation of novel cell types in the lung epithelium, including pulmonary ionocytes, may also encourage cell type-specific targeting for CF correction. We anticipate preclinical studies to further validate these strategies, which should pave the way for clinical trials. We also expect gene editing efficiencies to improve to clinically translatable levels, given advancements in viral and non-viral vectors. Overall, gene delivery technologies look more convincing in producing an effective CF gene therapy.

PMID: 31215818 [PubMed – as supplied by publisher]

PubMed:31215818

Ivacaftor was safe and effective in severe cystic fibrosis patients with non-G551D gating mutations

https://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.24424

https://www.ncbi.nlm.nih.gov/pubmed/31237430?dopt=Abstract

Related Articles

Effectivenesss of ivacaftor in severe cystic fibrosis patients and non-G551D gating mutations.

Pediatr Pulmonol. 2019 Jun 25;:

Authors: Salvatore D, Carnovale V, Iacotucci P, Braggion C, Castellani C, Cimino G, Colangelo C, Francalanci M, Leonetti G, Lucidi V, Manca A, Vitullo P, Ferrara N

Abstract

BACKGROUND: Ivacaftor is a significant innovation in the treatment of cystic fibrosis (CF) with gating mutations. A substantial percentage of patients with CF have severe lung involvement, but these patients are usually excluded from phase III clinical trials. Thus, the effectiveness of ivacaftor in this population has not been fully determined.

METHODS: Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use programme (percent predicted [pp] forced expiratory volume in 1 second [FEV1 ] < 40%, or on lung transplant waiting list, or with a fast worsening trend of lung function). Data were collected for 1 year before and 1 year after ivacaftor commencement. RESULTS: Thirteen patients received ivacaftor for a median of 320 days. Mean (SD) ppFEV1 increased from 35.1% (14.3%) before treatment to 46.6% (18.8%) after 12 months of treatment (absolute increase 11.5%, relative increase 32.8%). Mean distance of the 6-minute walking test improved significantly, from 535.1 m before to 611.6 m after 12 months of treatment (P = .002). The number of pulmonary exacerbations decreased significantly, from 57 during the year before ivacaftor to 28 in the year following ivacaftor (P = .0048). Five of the 13 patients (38.5%) had no exacerbations during the 12 months after starting ivacaftor. Median weight increased significantly, from 52.7 kg to 55.6 kg (P = .0031). Mean (SD) sweat chloride concentration decreased significantly, from 99.5 (22.8) mmol/L to 39.3 (15.8) mmol/L (P < .0001). No safety concerns were registered. CONCLUSIONS: Ivacaftor was safe and effective in patients with CF with severe lung disease and non-G551D gating mutations. PMID: 31237430 [PubMed - as supplied by publisher] PubMed:31237430

Human MesenchymAl Stem Cells Infusion in Patients With Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03058068?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=06%2F10%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Interventions :   Biological: Allo-hMSCs;   Biological: Placebo

Sponsor :   Joshua M Hare

Not yet recruiting

Human MesenchymAl Stem Cells Infusion in Patients With Cystic Fibrosis

NCT03058068

Mon, 20 Feb 2017 12:00:00 EST

Last Update Posted: 06/24/19 07:42AM

Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03251092?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=06%2F04%2F2019&lupd_d=14

Conditions :   Healthy Volunteer – Complete;   Cystic Fibrosis

Interventions :   Drug: PTI-808;   Drug: Placebo;   Drug: PTI-428;   Drug: PTI-801

Sponsor :   Proteostasis Therapeutics, Inc.

Recruiting

Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis

NCT03251092

Wed, 16 Aug 2017 12:00:00 EDT

Last Update Posted: 06/18/19 07:04AM

Cystic fibrosis drug ivacaftor (Vx-770) stimulates CFTR channels at picomolar concentrations

https://elifesciences.org/articles/46450

https://www.ncbi.nlm.nih.gov/pubmed/31205003?dopt=Abstract

Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations.

Elife. 2019 Jun 17;8:

Authors: Csanády L, Töröcsik B

Abstract

The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200-fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is >100-fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design of in vitro studies using Vx-770.

PMID: 31205003 [PubMed – as supplied by publisher]

PubMed:31205003

Airway regeneration using iPS cell-derived airway epithelial cells with Cl- channel function

https://www.tandfonline.com/doi/full/10.1080/19336950.2019.1628550

https://www.ncbi.nlm.nih.gov/pubmed/31198082?dopt=Abstract

Airway regeneration using iPS cell-derived airway epithelial cells with Cl- channel function.

Channels (Austin). 2019 Dec;13(1):227-234

Authors: Yoshie S, Omori K, Hazama A

Abstract

induced pluripotent stem (iPS) cells can be differentiated into various cell types, including airway epithelial cells, since they have the capacity for self-renewal and pluripotency. Thus, airway epithelial cells generated from iPS cells are expected to be potent candidates for use in airway regeneration and the treatment of airway diseases such as cystic fibrosis (CF). Recently, it was reported that iPS cells can be differentiated into airway epithelial cells according to the airway developmental process. These studies demonstrate that airway epithelial cells generated from iPS cells are equivalent to their in vivo counterparts. However, it has not been evaluated in detail whether these cells exhibit physiological functions and are fully mature. Airway epithelial cells adequately control water volume on the airway surface via the function of Cl- channels. Reasonable environments on the airway surface cause ciliary movement with a constant rhythm and maintain airway clearance. Therefore, the generation of functional airway epithelial cells/tissues with Cl- channel function from iPS cells will be indispensable for cell/tissue replacement therapy, the development of a reliable airway disease model, and the treatment of airway disease. This review highlights the generation of functional airway epithelial cells from iPS cells and discusses the remaining challenges to the generation of functional airway epithelial cells for airway regeneration and the treatment of airway disease.

PMID: 31198082 [PubMed – in process]

PubMed:31198082

Augmentation of CFTR function in human bronchial epithelial cells via SLC6A14-dependent amino acid uptake: Implications for treatment of Cystic Fibrosis

https://www.atsjournals.org/doi/10.1165/rcmb.2019-0094OC

https://www.ncbi.nlm.nih.gov/pubmed/31189070?dopt=Abstract

Augmentation of CFTR function in human bronchial epithelial cells via SLC6A14-dependent amino acid uptake: Implications for treatment of Cystic Fibrosis.

Am J Respir Cell Mol Biol. 2019 Jun 12;:

Authors: Ahmadi S, Wu YS, Li M, Ip W, Lloyd-Kuzik A, Di Paola M, Du K, Xia S, Lew A, Bozoky Z, Forman-Kay J, Bear CE, Gonska T

Abstract

RATIONALE: SLC6A14 mediated L-arginine transport has been shown to augment the residual anion channel activity of the major mutant, F508del-CFTR, in the murine gastrointestinal tract. It is not yet known if this transporter augments residual and pharmacological corrected F508del-CFTR in primary airway epithelia.

OBJECTIVE: To determine the role of L-arginine uptake via SLC6A14 in modifying F508del-CFTR channel activity in airway cells from CF patients.

METHODS: Human bronchial epithelial cells from lung explants of non-CF (HBE) and CF patients (CF-HBE) were used for H3-flux, airway surface liquid (ASL) and Ussing chamber studies. We used α-methyltryptophan (α-MT) as specific inhibitor for SLC6A14. CFBE41o-, a commonly used CF airway cell line, was employed for studying the mechanism of the functional interaction between SLC6A14 and F508del-CFTR.

MAIN RESULTS: SLC6A14 is functionally expressed in CF-HBE cells. L-arginine uptake via SLC6A14 augmented F508del-CFTR function at baseline and after treatment with lumacaftor. SLC6A14 mediated L-arginine uptake also increased the ASL in CF-HBE cells. Using CFBE41o cells we showed that the positive SLC6A14 effect was mainly dependent on the nitric oxide synthase activity, nitrogen oxides including nitric oxide (NO) and phosphorylation by protein kinase G. These finding were confirmed in CF-HBE as iNOS inhibition abrogated the functional interaction between SLC6A14 and pharmacological corrected F508del-CFTR.

CONCLUSION: SLC6A14-mediated L-arginine transport augments residual F508del-CFTR channel function via a non-canonical, NO pathway. This effect is enhanced with increasing pharmacological rescue of F508del-CFTR to the membrane. The current study demonstrates how endogenous pathways can be utilized for the development of companion therapy in CF.

PMID: 31189070 [PubMed – as supplied by publisher]

PubMed:31189070

Novel AAV-mediated gene delivery system corrects CFTR function in pigs

https://www.atsjournals.org/doi/10.1165/rcmb.2019-0006OC

https://www.ncbi.nlm.nih.gov/pubmed/31184507?dopt=Abstract

Novel AAV-mediated gene delivery system corrects CFTR function in pigs.

Am J Respir Cell Mol Biol. 2019 Jun 11;:

Authors: Cooney AL, Thornell IM, Singh BK, Shah VS, Stoltz DA, McCray PB, Zabner J, Sinn PL

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease caused by a mutant cystic fibrosis transmembrane conductance regulator (CFTR) gene and characterized by chronic bacterial lung infections and inflammation. Complementation with functional CFTR normalizes anion transport across the airway surface. Adeno-associated virus (AAV) is a useful vector for gene therapy because of its low immunogenicity and ability to persist for months to years. However, episomal expression may decrease following cell division and ultimately require readministration. To overcome this, we designed an integrating AAV-based CFTR expressing vector termed PB/AAV carrying CFTR flanked by the terminal repeats (TRs) of the piggyBac transposon. With co-delivery of piggyBac transposase, PB/AAV can integrate into the host genome. Because of the AAV packaging constraints, careful consideration was required to ensure that the vector would package and express its CFTR cDNA cargo. In this short-term study, PB/AAV-CFTR was aerosolized to the airways of CF pigs in the absence of the transposase. Two weeks later, transepithelial Cl- current was restored in freshly excised tracheal and bronchus tissue. Additionally, we observed an increase in tracheal airway surface liquid (ASL) pH and bacterial killing as compared to untreated CF pigs. ASL from primary airway cells cultured from treated CF pigs exhibited increased pH correlating with decreased viscosity. Together, these results show that complementing CFTR in CF pigs with PB/AAV rescues the anion transport defect in a large animal CF model. Delivery of this integrating viral vector system to airway progenitor cells could lead to persistent, life-long expression in vivo.

PMID: 31184507 [PubMed – as supplied by publisher]

PubMed:31184507

Glycerol Phenylbutyrate Corrector Therapy [Ravicti] For CF (Cystic Fibrosis)

https://clinicaltrials.gov/ct2/show/NCT02323100?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=05%2F28%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Interventions :   Drug: Ravicti low dose;   Drug: Ravicti high dose;   Drug: Placebo

Sponsors :   National Jewish Health;   University of Alabama at Birmingham;   Children’s Hospital of Philadelphia;   Johns Hopkins University;   Horizon Pharma Ireland, Ltd., Dublin Ireland

Recruiting

Glycerol Phenylbutyrate Corrector Therapy For CF (Cystic Fibrosis)

NCT02323100

Tue, 23 Dec 2014 12:00:00 EST

Last Update Posted: 06/11/19 07:02AM

Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis

https://www.cysticfibrosisjournal.com/article/S1569-1993(19)30766-0/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31182369?dopt=Abstract

Related Articles

Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis.

J Cyst Fibros. 2019 Jun 07;:

Authors: Drevinek P, Pressler T, Cipolli M, De Boeck K, Schwarz C, Bouisset F, Boff M, Henig N, Paquette-Lamontagne N, Montgomery S, Perquin J, Tomkinson N, den Hollander W, Elborn JS

Abstract

BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation.

METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS).

RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment.

CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.

PMID: 31182369 [PubMed – as supplied by publisher]

PubMed:31182369

Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability

https://www.frontiersin.org/articles/10.3389/fphar.2019.00619/full

https://www.ncbi.nlm.nih.gov/pubmed/31231217?dopt=Abstract

Related Articles

Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability.

Front Pharmacol. 2019;10:619

Authors: Loureiro CA, Santos JD, Matos AM, Jordan P, Matos P, Farinha CM, Pinto FR

Abstract

In cystic fibrosis, the most common disease-causing mutation is F508del, which causes not only intracellular retention and degradation of CFTR, but also defective channel gating and decreased membrane stability of the small amount that reaches the plasma membrane (PM). Thus, pharmacological correction of mutant CFTR requires targeting of multiple cellular defects in order to achieve clinical benefit. Although small-molecule compounds have been identified and commercialized that can correct its folding or gating, an efficient retention of F508del CFTR at the PM has not yet been explored pharmacologically despite being recognized as a crucial factor for improving functional rescue of chloride transport. In ongoing efforts to determine the CFTR interactome at the PM, we used three complementary approaches: targeting proteins binding to tyrosine-phosphorylated CFTR, protein complexes involved in cAMP-mediated CFTR stabilization at the PM, and proteins selectively interacting at the PM with rescued F508del-CFTR but not wt-CFTR. Using co-immunoprecipitation or peptide-pull down strategies, we identified around 400 candidate proteins through sequencing of complex protein mixtures using the nano-LC Triple TOF MS technique. Key candidate proteins were validated for their robust interaction with CFTR-containing protein complexes and for their ability to modulate the amount of CFTR expressed at the cell surface of bronchial epithelial cells. Here, we describe how we explored the abovementioned experimental datasets to build a protein interaction network with the aim of identifying novel pharmacological targets to rescue CFTR function in cystic fibrosis (CF) patients. We identified and validated novel candidate proteins that were essential components of the network but not detected in previous proteomic analyses.

PMID: 31231217 [PubMed]

PubMed:31231217

A Phase 2 Study of ABBV-3067 Alone and in Combination With ABBV-2222

https://clinicaltrials.gov/ct2/show/NCT03969888?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=05%2F17%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Interventions :   Drug: ABBV-3067;   Drug: Placebo ABBV-3067;   Drug: ABBV-2222;   Drug: Placebo ABBV-2222

Sponsor :   AbbVie

Not yet recruiting

A Phase 2 Study of ABBV-3067 Alone and in Combination With ABBV-2222

NCT03969888

Fri, 31 May 2019 12:00:00 EDT

Last Update Posted: 05/31/19 07:15AM

Focus on TRP channels in cystic fibrosis

https://www.ncbi.nlm.nih.gov/pubmed/31176886?dopt=Abstract

Focus on TRP channels in cystic fibrosis.

Cell Calcium. 2019 May 30;81:29-37

Authors: Grebert C, Becq F, Vandebrouck C

Abstract

The Transient Receptor Potential (TRP) protein superfamily is a group of cation channels expressed in various cell types and involved in respiratory diseases such as cystic fibrosis (CF), the genetic disease caused by CF Transmembrane conductance Regulator (CFTR) mutations. In human airway epithelial cells, there is growing evidence for a functional link between CFTR and TRP channels. TRP channels contribute to transmitting extracellular signals into the cells and, in an indirect manner, to CFTR activity via a Ca2+ rise signaling. Indeed, mutated CFTR-epithelial cells are characterized by an increased Ca2+ influx and, on the opposite, by a decreased of magnesium influx, both being mediated by TRP channels. This increasing cellular Ca2+ triggers the activation of calcium-activated chloride channels (CaCC) or CFTR itself, via adenylyl cyclase, PKA and tyrosine kinases activation, but also leads to an exaltation of the inflammatory response. Another shortcoming in mutated CFTR-epithelial cells is a [Mg2+]i decrease, associated with impaired TRPM7 functioning. This deregulation has to be taken into consideration in CF physiopathology, as Mg2+ is required for ATP hydrolysis and CFTR activity. The modulation of druggable TRP channels could supplement CF therapy either an anti-inflammatory drug or for CFTR potentiation, according to the balance between exacerbation and respite phases. The present paper focus on TRPA1, TRPC6, TRPM7, TRPV2, TRPV4, TRPV6 and ORAI 1, the proteins identified, for now, as dysfunctional channels, in CF cells.

PMID: 31176886 [PubMed – as supplied by publisher]

PubMed:31176886

Antibiofilm efficacy of nitric oxide-releasing alginates against cystic fibrosis bacterial pathogens

https://pubs.acs.org/doi/10.1021/acsinfecdis.9b00016

https://www.ncbi.nlm.nih.gov/pubmed/31136714?dopt=Abstract

Antibiofilm efficacy of nitric oxide-releasing alginates against cystic fibrosis bacterial pathogens.

ACS Infect Dis. 2019 May 28;:

Authors: Ahonen MJR, Dorrier JM, Schoenfisch MH

Abstract

Colonization of the lungs by biofilm-forming pathogens is a major cause of mortality in cystic fibrosis (CF). In CF patients, these pathogens are difficult to treat due to the additional protection provided by both the biofilm exopolysaccharide matrix and thick, viscous mucus. The antibiofilm efficacy of nitric oxide (NO)-releasing alginates were evaluated against Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococcus aureus, and methicillin-resistant S. aureus biofilms in both aerobic and anaerobic environments. Varying the amine precursor grafted onto alginate oligosaccharides imparted tunable NO storage (~0.1-0.3 µmol/mg) and release kinetics (~4-40 min half-lives) in the artificial sputum media used for biofilm testing. The NO-releasing alginates were highly antibacterial against the four CF-relevant pathogens, achieving a 5-log reduction in biofilm viability after 24-h treatment, with biocidal efficacy dependent on NO-release kinetics. Aerobic biofilms required greater starting NO doses to achieve killing relative to the anaerobic biofilms. Relative to tobramycin (MBEC24h ≥2000 µg/mL) and vancomycin (MBEC24h ≥1000 µg/mL), the NO-releasing alginates proved to be more effective (NO dose ≤520 µg/mL) regardless of growth conditions.

PMID: 31136714 [PubMed – as supplied by publisher]

PubMed:31136714

Novel Therapeutic Approaches for Treatment of CF Patients With W1282X Premature Termination Codon Mutations

https://clinicaltrials.gov/ct2/show/NCT03624101?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=05%2F03%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Intervention :   Drug: Tezacaftor/Ivacaftor

Sponsor :   University of Alabama at Birmingham

Recruiting

Novel Therapeutic Approaches for Treatment of CF Patients With W1282X Premature Termination Codon Mutations

NCT03624101

Thu, 09 Aug 2018 12:00:00 EDT

Last Update Posted: 05/17/19 07:16AM

Cystic Fibrosis Patients Turn to Experimental Phage Therapy

https://www.nytimes.com/2019/05/17/well/live/cystic-fibrosis-patients-turn-to-experimental-phage-therapy.html

http://archive.is/sjG3o#selection-257.0-261.134

Cystic Fibrosis Patients Turn to Experimental Phage Therapy

Phages have not been approved by the Food and Drug Administration, but there is growing interest in the treatment for cystic fibrosis.

L-iminosugars show therapeutic potential as anti-inflammatory agents in cystic fibrosis

An excerpt from a recent paper (April 25, 2019) titled, Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease:

Biological results herein obtained place ent-1 and congeners among the earliest examples of l-iminosugars acting as anti-inflammatory agents for therapeutic applications in Cystic Fibrosis.

The paper describes how certain iminosugars were able to dramatically reduce the inflammatory response induced by P. aeruginosa… and do it extremely efficiently:

The remarkably low dosage [40-fold vs. counterpart] of the l-iminosugar, combined with its inability to act as inhibitor for most glycosidases, is expected to limit the onset of undesired effects, which are typically associated with the administration of its d-counterpart.

For more information, check out the recent paper (links below).

https://www.sciencedirect.com/science/article/pii/S0223523419303794

https://www.ncbi.nlm.nih.gov/pubmed/31075609?dopt=Abstract

Further reading on iminosugars:

https://en.wikipedia.org/wiki/Iminosugar

A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis

https://www.ncbi.nlm.nih.gov/pubmed/31076617?dopt=Abstract

Related Articles

A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis.

Sci Rep. 2019 May 10;9(1):7234

Authors: Habib AR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS

Abstract

Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV1% predicted (ppFEV1). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.

PMID: 31076617 [PubMed – in process]

PubMed:31076617

A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-001862-56

EudraCT Number: 2017-001862-56

Sponsor Protocol Number: 64041575RSV2004

Sponsor Name: Janssen-Cilag International NV

Start Date: 2018-01-09

Medical condition: Respiratory syncytial virus infection

Disease:

Version: 20.0

SOC Term: 10021881 – Infections and infestations

Classification Code: 10061603

Term: Respiratory syncytial virus infection

Level: PT

Population Age: Infants and toddlers, Children, Under 18

Gender: Male, Female

Trial Protocol: GB (Ongoing), DE (Prematurely Ended), BE (Prematurely Ended), FI (Prematurely Ended), SK (Prematurely Ended), ES (Prematurely Ended), IE (Prematurely Ended), PT (Prematurely Ended), FR (Prematurely Ended), IT (Temporarily Halted)

A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine (…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-001862-56

Last Update Posted: 05/10/19 09:44AM

Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators

https://www.ncbi.nlm.nih.gov/pubmed/31143125?dopt=Abstract

https://www.frontiersin.org/articles/10.3389/fphar.2019.00514/full

Related Articles

Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators.

Front Pharmacol. 2019;10:514

Authors: de Wilde G, Gees M, Musch S, Verdonck K, Jans M, Wesse AS, Singh AK, Hwang TC, Christophe T, Pizzonero M, Van der Plas S, Desroy N, Cowart M, Stouten P, Nelles L, Conrath K

Abstract

The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide experimental evidence that the clinical candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.

PMID: 31143125 [PubMed]

PubMed:31143125

A Phase 3, Open-label, Rollover Study to Evaluate the Safety and Efficacy of Long term Treatment With VX 661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004827-29

EudraCT Number: 2014-004827-29

Sponsor Protocol Number: VX14-661-110

Sponsor Name: Vertex Pharmaceuticals Incorporated

Start Date: 2015-09-01

Medical condition: Cystic Fibrosis

Disease:

Version: 18.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Adolescents, Under 18, Adults

Gender: Male, Female

Trial Protocol: IT (Ongoing), IE (Ongoing), GB (Ongoing), BE (Ongoing), SE (Ongoing), AT (Completed), DK (Ongoing), NL (Ongoing), DE (Ongoing), ES (Completed)

A Phase 3, Open-label, Rollover Study to Evaluate the Safety and Efficacy of Long term Treatment With VX 661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, …

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004827-29

Last Update Posted: 05/06/19 11:34AM

Great Strides Being Made in Treating Cystic Fibrosis

https://www.kaaltv.com/news/great-strides-being-made-in-treating-cystic-fibrosis/5341778/

By next year, another drug cocktail is expected to be available. “Over 90% of cystic fibrosis patients will finally have a drug that is moderately-effective to significantly-effective at improving their outcome,” said Dr. Wylam.

Dose Escalation Study of ALX-009 in Healthy Men and Cystic Fibrosis (CF) and Non-CF Bronchiectasis Patients

https://clinicaltrials.gov/ct2/show/NCT02598999?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=04%2F17%2F2019&lupd_d=14

Conditions :   Cystic Fibrosis;   Bronchiectasis

Interventions :   Drug: ALX-009;   Drug: OSCN-;   Drug: bLF;   Drug: Placebo

Sponsor :   Alaxia SAS

Recruiting

Dose Escalation Study of ALX-009 in Healthy Men and Cystic Fibrosis (CF) and Non-CF Bronchiectasis Patients

NCT02598999

Fri, 06 Nov 2015 12:00:00 EST

Last Update Posted: 05/01/19 07:29AM

A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000184-89

EudraCT Number: 2018-000184-89

Sponsor Protocol Number: VX17-445-103

Sponsor Name: Vertex Pharmaceuticals Incorporated

Start Date: 2018-09-07

Medical condition:

Disease:

Version: 20.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Adolescents, Under 18, Adults

Gender: Male, Female

Trial Protocol: BE (Completed), NL (Ongoing)

A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation (…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000184-89

Last Update Posted: 05/01/19 05:56AM

Structural analogues of roscovitine rescue the intracellular traffic and the function of ER-retained ABCB4 variants in cell models

https://www.nature.com/articles/s41598-019-43111-y

https://www.ncbi.nlm.nih.gov/pubmed/31040306?dopt=Abstract

Related Articles

Structural analogues of roscovitine rescue the intracellular traffic and the function of ER-retained ABCB4 variants in cell models.

Sci Rep. 2019 Apr 30;9(1):6653

Authors: Vauthier V, Ben Saad A, Elie J, Oumata N, Durand-Schneider AM, Bruneau A, Delaunay JL, Housset C, Aït-Slimane T, Meijer L, Falguières T

Abstract

Adenosine triphosphate binding cassette transporter, subfamily B member 4 (ABCB4) is the transporter of phosphatidylcholine at the canalicular membrane of hepatocytes. ABCB4 deficiency, due to genetic variations, is responsible for progressive familial intrahepatic cholestasis type 3 (PFIC3) and other rare biliary diseases. Roscovitine is a molecule in clinical trial that was shown to correct the F508del variant of cystic fibrosis transmembrane conductance regulator (CFTR), another ABC transporter. In the present study, we hypothesized that roscovitine could act as a corrector of ABCB4 traffic-defective variants. Using HEK and HepG2 cells, we showed that roscovitine corrected the traffic and localisation at the plasma membrane of ABCB4-I541F, a prototypical intracellularly retained variant. However, roscovitine caused cytotoxicity, which urged us to synthesize non-toxic structural analogues. Roscovitine analogues were able to correct the intracellular traffic of ABCB4-I541F in HepG2 cells. Importantly, the phospholipid secretion activity of this variant was substantially rescued by three analogues (MRT2-235, MRT2-237 and MRT2-243) in HEK cells. We showed that these analogues also triggered the rescue of intracellular traffic and function of two other intracellularly retained ABCB4 variants, i.e. I490T and L556R. Our results indicate that structural analogues of roscovitine can rescue genetic variations altering the intracellular traffic of ABCB4 and should be considered as therapeutic means for severe biliary diseases caused by this class of variations.

PMID: 31040306 [PubMed – in process]

PubMed:31040306

Restoration of F508-del Function by Transcomplementation: The Partners Meet in the Endoplasmic Reticulum – “These results come at an opportune time for developing a gene therapy for CF and offer new treatment options for a wide range of CF patients.”

hhttps://www.cellphysiolbiochem.com/Articles/000089/

ttps://www.ncbi.nlm.nih.gov/pubmed/31026390?dopt=Abstract

Restoration of F508-del Function by Transcomplementation: The Partners Meet in the Endoplasmic Reticulum.

Cell Physiol Biochem. 2019;52(6):1267-1279

Authors: Bergbower EAS, Sabirzhanova I, Boinot C, Guggino WB, Cebotaru L

Abstract

BACKGROUND/AIMS: Because of the small size of adeno-associated virus, AAV, the cystic fibrosis conductance regulator, CFTR, cDNA is too large to fit within AAV and must be truncated. We report here on two truncated versions of CFTR, which, when inserted into AAV1 and used to infect airway cells, rescue F508-del CFTR via transcomplementation. The purpose of this study is to shed light on where in the cell transcomplementation occurs and how it results in close association between the endogenous F508-del and truncated CFTR.

METHODS: We treated CF airway cells (CFBE41o-) with AAV2/1 (AAV2 inverted terminal repeats/AAV1 capsid) containing truncated forms of CFTR, ∆264 and ∆27-264 CFTR, who can restore the function of F508-del by transcomplementation. We addressed the aims of the study using a combination of confocal microscopy and short circuit currents measurements. For the latter, CF bronchial epithelial cells (CFBE) were grown on permeable supports.

RESULTS: We show that both F508del and the truncation mutants colocalize in the ER and that both the rescued F508-del and the transcomplementing mutants reach the plasma membrane together. There was significant fluorescence resonance energy transfer (FRET) between F508-del and the transcomplementing mutants within the endoplasmic reticulum (ER), suggesting that transcomplementation occurs through a bimolecular interaction. We found that transcomplementation could increase the Isc in CFBE41o- cells stably expressing additional wt-CFTR or F508-del and in parental CFBE41o- cells expressing endogenous levels of F508-del.

CONCLUSION: We conclude that the functional rescue of F508-del by transcomplementation occurs via a bimolecular interaction that most likely begins in the ER and continues at the plasma membrane. These results come at an opportune time for developing a gene therapy for CF and offer new treatment options for a wide range of CF patients.

PMID: 31026390 [PubMed – in process]

PubMed:31026390

Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease

https://www.ncbi.nlm.nih.gov/pubmed/31075609?dopt=Abstract

Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease.

Eur J Med Chem. 2019 Apr 25;175:63-71

Authors: De Fenza M, D’Alonzo D, Esposito A, Munari S, Loberto N, Santangelo A, Lampronti I, Tamanini A, Rossi A, Ranucci S, De Fino I, Bragonzi A, Aureli M, Bassi R, Tironi M, Lippi G, Gambari R, Cabrini G, Palumbo G, Dechecchi MC, Guaragna A

Abstract

In the frame of a research program aimed to explore the relationship between chirality of iminosugars and their therapeutic potential, herein we report the synthesis of N-akyl l-deoxyiminosugars and the evaluation of the anti-inflammatory properties of selected candidates for the treatment of Pseudomonas aeruginosa infections in Cystic Fibrosis (CF) lung disease. Target glycomimetics were prepared by the shortest and most convenient approach reported to date, relying on the use of the well-known PS-TPP/I2 reagent system to prepare reactive alkoxyalkyl iodides, acting as key intermediates. Iminosugars ent-1-3 demonstrated to efficiently reduce the inflammatory response induced by P. aeruginosa in CuFi cells, either alone or in synergistic combination with their d-enantiomers, by selectively inhibiting NLGase. Surprisingly, the evaluation in murine models of lung disease showed that the amount of ent-1 required to reduce the recruitment of neutrophils was 40-fold lower than that of the corresponding d-enantiomer. The remarkably low dosage of the l-iminosugar, combined with its inability to act as inhibitor for most glycosidases, is expected to limit the onset of undesired effects, which are typically associated with the administration of its d-counterpart. Biological results herein obtained place ent-1 and congeners among the earliest examples of l-iminosugars acting as anti-inflammatory agents for therapeutic applications in Cystic Fibrosis.

PMID: 31075609 [PubMed – as supplied by publisher]

PubMed:31075609

A Phase IIa, Randomized, Placebo-controlled, Double-blind, Cross-over Study to Evaluate Safety and Efficacy of Subcutaneous Administration of Anakinra in Patients With Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03925194?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=04%2F10%2F2019&lupd_d=14

Condition :   Cystic Fibrosis, 10011762

Intervention :   Drug: Anakinra

Sponsor :   Heidelberg University

Not yet recruiting

A Phase IIa, Randomized, Placebo-controlled, Double-blind, Cross-over Study to Evaluate Safety and Efficacy of Subcutaneous Administration of Anakinra in Patients With Cystic Fibrosis

NCT03925194

Wed, 24 Apr 2019 12:00:00 EDT

Last Update Posted: 04/24/19 07:50AM

Impact of CFTR-modulating drugs on GH-IGF-1 axis impairment in adult patients with cystic fibrosis.

https://link.springer.com/article/10.1007%2Fs40618-019-01051-4

https://www.ncbi.nlm.nih.gov/pubmed/31006073?dopt=Abstract

Impact of CFTR-modulating drugs on GH-IGF-1 axis impairment in adult patients with cystic fibrosis.

J Endocrinol Invest. 2019 Apr 20;:

Authors: Pascucci C, De Biase RV, Savi D, Quattrucci S, Gnessi L, Lubrano C, Lenzi A

Abstract

INTRODUCTION: A new class of drugs in the treatment of cystic fibrosis (CF) includes two agents: lumacaftor, which corrects CFTR channel protein, and ivacaftor, which increases CFTR channel activity. In our previous study we recruited 50 stable adults with CF and 16 of them showed growth hormone deficit (GHD): 7 patients severe and 9 patients partial GHD.

MATERIAL AND METHODS: We decided to re-evaluate ten patients with the GHRH + arginine test of whom only five were treated with lumacaftor/ivacaftor.

RESULTS: All CF patients in therapy with lumacaftor/ivacaftor showed a marked improvement in GHD. Two patients moved from a severe GHD to a normal response to the GH/IGF-1 axis test, and three patients who had partial GHD moved to normal response.

CONCLUSION: The pituitary gland may be damaged by CF disease and could benefit of the action of correcting drugs.

PMID: 31006073 [PubMed – as supplied by publisher]

PubMed:31006073

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial to Evaluate Efficacy and Safety of Lenabasum in Cystic Fibrosis

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003723-29

EudraCT Number: 2017-003723-29

Sponsor Protocol Number: JBT101-CF-002

Sponsor Name: Corbus Pharmaceuticals, Inc.

Start Date: 2018-11-19

Medical condition: Cystic Fibrosis (CF)

Disease:

Version: 20.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Adolescents, Under 18, Adults

Gender: Male, Female

Trial Protocol: DE (Ongoing), HU (Ongoing), SE (Ongoing), FR (), PT (Ongoing), SK (Ongoing), AT (Ongoing), BE (Ongoing), ES (Ongoing), BG (), NL (Ongoing), CZ (Ongoing), GR (Ongoing)

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial to Evaluate Efficacy and Safety of Lenabasum in Cystic Fibrosis

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003723-29

Last Update Posted: 04/18/19 08:50AM

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center Study to Assess the Efficacy, Safety and Tolerability, and Pharmacokinetics of INS1007 Administered Once Daily for 24 We…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002533-32

EudraCT Number: 2017-002533-32

Sponsor Protocol Number: INS1007-201

Sponsor Name: Insmed Incorporated

Start Date: 2018-03-15

Medical condition: Non-Cystic Fibrosis Bronchiectasis

Disease:

Version: 20.0

SOC Term: 10038738 – Respiratory, thoracic and mediastinal disorders

Classification Code: 10038738

Term: Respiratory, thoracic and mediastinal disorders

Level: SOC

Version: 20.1

SOC Term: 10038738 – Respiratory, thoracic and mediastinal disorders

Classification Code: 10006445

Term: Bronchiectasis

Level: PT

Population Age: Adults, Elderly

Gender: Male, Female

Trial Protocol: DE (Ongoing), SE (Ongoing), ES (Ongoing), NL (Ongoing), BG (Ongoing), PL (Ongoing), BE (Ongoing)

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center Study to Assess the Efficacy, Safety and Tolerability, and Pharmacokinetics of INS1007 Administered Once Daily for 24 We…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002533-32

Last Update Posted: 04/17/19 06:26AM

A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004132-11

EudraCT Number: 2017-004132-11

Sponsor Protocol Number: VX17-659-102

Sponsor Name: Vertex Pharmaceuticals Incorporated

Start Date: 2018-04-25

Medical condition: Cystic fibrosis

Disease:

Version: 20.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Adolescents, Under 18, Adults

Gender: Male, Female

Trial Protocol: DE (Completed), DK (Completed), IE (Ongoing), ES (Completed), PL ()

A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004132-11

Last Update Posted: 04/17/19 03:59AM

iPS Cell Response to CFTR Modulators

https://clinicaltrials.gov/ct2/show/NCT03506061?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=04%2F02%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Intervention :   Drug: Orkambi

Sponsors :   Emory University;   National Heart, Lung, and Blood Institute (NHLBI)

Not yet recruiting

iPS Cell Response to CFTR Modulators

NCT03506061

Mon, 23 Apr 2018 12:00:00 EDT

Last Update Posted: 04/16/19 09:05AM

A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004134-29

EudraCT Number: 2017-004134-29

Sponsor Protocol Number: VX17-659-105

Sponsor Name: Vertex Pharmaceuticals Incorporated

Start Date: Information not available in EudraCT

Medical condition: Cystic fibrosis

Disease:

Version: 20.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Adolescents, Under 18, Adults

Gender: Male, Female

Trial Protocol: DE (), IE (Ongoing), ES (Ongoing), DK (Ongoing), PL (Ongoing)

A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004134-29

Last Update Posted: 04/16/19 09:31AM

A multicenter, open-label Phase 2 study with escalating doses of MS1819-SD on top of a stable dose of PPEs, to investigate the efficacy and safety of this combination for the compensation of severe…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003831-31

EudraCT Number: 2018-003831-31

Sponsor Protocol Number: MS1819/18/02

Sponsor Name: AzurRx

Start Date: 2019-03-28

Medical condition: Exocrine Pancreatic Insufficiency

Disease:

Version: 20.0

SOC Term: 100000004856

Classification Code: 10033628

Term: Pancreatic insufficiency

Level: LLT

Population Age: Adolescents, Under 18, Adults

Gender: Male, Female

Trial Protocol: HU (Ongoing)

A multicenter, open-label Phase 2 study with escalating doses of MS1819-SD on top of a stable dose of PPEs, to investigate the efficacy and safety of this combination for the compensation of severe…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003831-31

Last Update Posted: 04/16/19 05:29AM

AMPs as Anti-biofilm Agents for Human Therapy and Prophylaxis

https://link.springer.com/chapter/10.1007%2F978-981-13-3588-4_14

https://www.ncbi.nlm.nih.gov/pubmed/30980362?dopt=Abstract

Related Articles

AMPs as Anti-biofilm Agents for Human Therapy and Prophylaxis.

Adv Exp Med Biol. 2019;1117:257-279

Authors: Shahrour H, Ferrer-Espada R, Dandache I, Bárcena-Varela S, Sánchez-Gómez S, Chokr A, Martínez-de-Tejada G

Abstract

Microbial cells show a strong natural tendency to adhere to surfaces and to colonize them by forming complex communities called biofilms. In this growth mode, biofilm-forming cells encase themselves inside a dense matrix which efficiently protects them against antimicrobial agents and effectors of the immune system. Moreover, at the physiological level, biofilms contain a very heterogeneous cell population including metabolically inactive organisms and persisters, which are highly tolerant to antibiotics. The majority of human infectious diseases are caused by biofilm-forming microorganisms which are responsible for pathologies such as cystic fibrosis, infective endocarditis, pneumonia, wound infections, dental caries, infections of indwelling devices, etc. AMPs are well suited to combat biofilms because of their potent bactericidal activity of broad spectrum (including resting cells and persisters) and their ability to first penetrate and then to disorganize these structures. In addition, AMPs frequently synergize with antimicrobial compounds and were recently reported to repress the molecular pathways leading to biofilm formation. Finally, there is a very active research to develop AMP-containing coatings that can prevent biofilm formation by killing microbial cells on contact or by locally releasing their active principle. In this chapter we will describe these strategies and discuss the perspectives of the use of AMPs as anti-biofilm agents for human therapy and prophylaxis.

PMID: 30980362 [PubMed – in process]

PubMed:30980362

A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects With Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03912233?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F28%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Interventions :   Drug: VX-121;   Drug: TEZ;   Drug: VX-561;   Drug: TEZ/IVA;   Drug: IVA;   Drug: Placebo

Sponsor :   Vertex Pharmaceuticals Incorporated

Not yet recruiting

A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects With Cystic Fibrosis

NCT03912233

Thu, 11 Apr 2019 12:00:00 EDT

Last Update Posted: 04/11/19 08:16AM

A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03911713?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F28%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Interventions :   Drug: VX-561;   Drug: IVA;   Drug: Placebo

Sponsor :   Vertex Pharmaceuticals Incorporated

Not yet recruiting

A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis

NCT03911713

Thu, 11 Apr 2019 12:00:00 EDT

Last Update Posted: 04/11/19 08:16AM

Beta-cell Response to Incretin Hormones in Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT01851694?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F27%2F2019&lupd_d=14

Conditions :   Cystic Fibrosis;   Pancreatic Insufficiency

Interventions :   Drug: GLP-1;   Drug: GIP

Sponsors :   University of Pennsylvania;   Children’s Hospital of Philadelphia

Recruiting

Beta-cell Response to Incretin Hormones in Cystic Fibrosis

NCT01851694

Fri, 10 May 2013 12:00:00 EDT

Last Update Posted: 04/10/19 08:33AM

A double-blind, placebo controlled, multicentre, clinical trial to investigate the efficacy and safety of 12 months of therapy with inhaled Promixin® (colistimethate sodium)

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004558-13

EudraCT Number: 2016-004558-13

Sponsor Protocol Number: Z7224L02

Sponsor Name: Zambon S.p.A.

Start Date: 2017-05-30

Medical condition: Non-cystic fibrosis bronchiectasis chronically infected with Pseudomonas aeruginosa

Disease:

Version: 19.1

SOC Term: 10038738 – Respiratory, thoracic and mediastinal disorders

Classification Code: 10006445

Term: Bronchiectasis

Level: PT

Population Age: Adults, Elderly

Gender: Male, Female

Trial Protocol: FR (Ongoing), PL (Ongoing)

A double-blind, placebo controlled, multicentre, clinical trial to investigate the efficacy and safety of 12 months of therapy with inhaled Promixin® (colistimethate sodium) in the treatment of sub…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004558-13

Last Update Posted: 04/10/19 05:57AM

Microbial Metabolites in Cystic Fibrosis: a Target for Future Therapy?

https://www.ncbi.nlm.nih.gov/pubmed/30965015?dopt=Abstract

Microbial Metabolites in Cystic Fibrosis: a Target for Future Therapy?

Am J Respir Cell Mol Biol. 2019 Apr 09;:

Authors: Widder S, Knapp S

PMID: 30965015 [PubMed – as supplied by publisher]

PubMed:30965015

Antibacterial Properties and Efficacy of a Novel SPLUNC1-Derived Antimicrobial Peptide, α4-Short, in a Murine Model of Respiratory Infection

https://mbio.asm.org/content/10/2/e00226-19

https://www.ncbi.nlm.nih.gov/pubmed/30967458?dopt=Abstract

Related Articles

Antibacterial Properties and Efficacy of a Novel SPLUNC1-Derived Antimicrobial Peptide, α4-Short, in a Murine Model of Respiratory Infection.

MBio. 2019 Apr 09;10(2):

Authors: Jiang S, Deslouches B, Chen C, Di ME, Di YP

Abstract

Multidrug resistance (MDR) by bacterial pathogens constitutes a global health crisis, and resistance to treatment displayed by biofilm-associated infections (e.g., cystic fibrosis, surgical sites, and medical implants) only exacerbates a problem that is already difficult to overcome. Antimicrobial peptides (AMPs) are a promising class of therapeutics that may be useful in the battle against antibiotic resistance, although certain limitations have hindered their clinical development. The goal of this study was to examine the therapeutic potential of novel AMPs derived from the multifunctional respiratory host defense protein SPLUNC1. Using standard growth inhibition and antibiofilm assays, we demonstrated that a novel structurally optimized AMP, α4-short, was highly effective against the most common group of MDR bacteria while showing broad-spectrum bactericidal and antibiofilm activities. With negligible hemolysis and toxicity to white blood cells, the new peptide also demonstrated in vivo efficacy when delivered directly into the airway in a murine model of Pseudomonas aeruginosa-induced respiratory infection. The data warrant further exploration of SPLUNC1-derived AMPs with optimized structures to assess the potential application to difficult-to-cure biofilm-associated infections.IMPORTANCE The rise of superbugs underscores the urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs) have the ability to kill superbugs regardless of resistance to traditional antibiotics. However, AMPs often display a lack of efficacy in vivo. Sequence optimization and engineering are promising but may result in increased host toxicity. We report here the optimization of a novel AMP (α4-short) derived from the multifunctional respiratory protein SPLUNC1. The AMP α4-short demonstrated broad-spectrum activity against superbugs as well as in vivo efficacy in the P. aeruginosa pneumonia model. Further exploration for clinical development is warranted.

PMID: 30967458 [PubMed – in process]

PubMed:30967458

Functional effects of the microbiota in chronic respiratory disease

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30510-1/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/30975495?dopt=Abstract

Related Articles

Functional effects of the microbiota in chronic respiratory disease.

Lancet Respir Med. 2019 Apr 08;:

Authors: Budden KF, Shukla SD, Rehman SF, Bowerman KL, Keely S, Hugenholtz P, Armstrong-James DPH, Adcock IM, Chotirmall SH, Chung KF, Hansbro PM

Abstract

The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research.

PMID: 30975495 [PubMed – as supplied by publisher]

PubMed:30975495

Study of VX-121 in Healthy Subjects and in Subjects With Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03768089?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F25%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Interventions :   Drug: VX-121;   Drug: TEZ/IVA;   Drug: IVA;   Drug: Matched Placebo

Sponsor :   Vertex Pharmaceuticals Incorporated

Active, not recruiting

Study of VX-121 in Healthy Subjects and in Subjects With Cystic Fibrosis

NCT03768089

Fri, 07 Dec 2018 12:00:00 EST

Last Update Posted: 04/08/19 08:27AM

Cytomegalovirus – an unrecognised potential contributor to cystic fibrosis disease progression?

https://erj.ersjournals.com/content/early/2019/01/16/13993003.01727-2018

https://www.ncbi.nlm.nih.gov/pubmed/30956206?dopt=Abstract

Related Articles

Cytomegalovirus – an unrecognised potential contributor to cystic fibrosis disease progression?

Eur Respir J. 2019 Apr 07;:

Authors: Parkins MD, Ramos KJ, Goss CH, Somayaji R

Abstract

Cytomegalovirus (CMV) is a common human beta-herpes virus most notable for causing visceral disease in profoundly immune-suppressed populations, and congenital infections. However, an increasing body of work has demonstrated that CMV seropositivity is associated with a number of chronic medical conditions including heart disease and dementia – potentially related to the effects of chronic inflammation. We hypothesided that the outcomes of individuals with cystic fibrosis (CF), a chronic inflammatory disease, could similarly be associated with CMV-status. We performed a single-centre retrospective study of all 71 individuals with CF referred for lung transplantation from our CF centre between 1991-2017 and assessed how CMV serostatus associated with patient pre-transplant outcomes. We observed CMV IgG positivity was associated with disproportionate progression to end-stage lung disease as defined by death/or transplantation in our cohort (27.2 versus 35.1 years, difference 7.95 (95% CI 3.61-12.29 years), p<0.001) which remained significant following adjustment for confounders (difference 6.96 (95% CI 2.51-11.41 years). CMV may represent a potentially important modifier of CF lung disease, warranting further study. PMID: 30956206 [PubMed - as supplied by publisher] PubMed:30956206

A Phase 3, Double-blind, Parallel-group Study to Evaluate the Efficacy and Safety of Tezacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With Cystic Fibrosis, Homozygous or…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004479-35

EudraCT Number: 2016-004479-35

Sponsor Protocol Number: VX16-661-115

Sponsor Name: Vertex Pharmaceuticals Incorporated

Start Date: Information not available in EudraCT

Medical condition: Cystic Fibrosis

Disease:

Version: 20.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Children, Under 18

Gender: Male, Female

Trial Protocol: IE (Completed), DK (Completed), BE (Completed), DE (Completed), PL (Ongoing), FR (Completed)

A Phase 3, Double-blind, Parallel-group Study to Evaluate the Efficacy and Safety of Tezacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With Cystic Fibrosis, Homozygous or…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004479-35

Last Update Posted: 04/06/19 04:35AM

Most important clinical papers in cystic fibrosis published in 2018 – with focus on CFTR modulator therapy

https://www.ncbi.nlm.nih.gov/pubmed/31053358?dopt=Abstract

Related Articles

Clinical papers of the year 2018 – Cystic fibrosis.

Paediatr Respir Rev. 2019 Apr 05;:

Authors: Balfour-Lynn IM

Abstract

This paper reviews the most important clinical papers in cystic fibrosis published in 2018, having searched all the literature on Pubmed. Focus is on CFTR modulator therapy, randomised controlled trials, and infection/microbiology issues.

PMID: 31053358 [PubMed – as supplied by publisher]

PubMed:31053358

A randomized, blinded, parallel group, multi-center dose-finding study, to assess the efficacy, safety and tolerability of different doses of tobramycin inhalation powder in patients with Non-Cysti…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003040-39

EudraCT Number: 2015-003040-39

Sponsor Protocol Number: CTBM100G2202

Sponsor Name: Novartis Pharma Services AG

Start Date: 2016-09-29

Medical condition: Pseudomonas aeruginosa infection in patients with non-cystic fibrosis bronchiectasis

Disease:

Version: 19.0

SOC Term: 10038738 – Respiratory, thoracic and mediastinal disorders

Classification Code: 10006445

Term: Bronchiectasis

Level: PT

Version: 19.0

SOC Term: 10021881 – Infections and infestations

Classification Code: 10070295

Term: Infective exacerbation of bronchiectasis

Level: PT

Population Age: Adults, Elderly

Gender: Male, Female

Trial Protocol: ES (Ongoing), BE (Completed), DE (Ongoing), IE (Temporarily Halted), NL (Ongoing), GB (Ongoing), IT (Temporarily Halted)

A randomized, blinded, parallel group, multi-center dose-finding study, to assess the efficacy, safety and tolerability of different doses of tobramycin inhalation powder in patients with Non-Cysti…

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003040-39

Last Update Posted: 04/05/19 08:21AM

A randomized, double blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of inhaled QBW276 in patients with cystic fibrosis

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004915-35

EudraCT Number: 2014-004915-35

Sponsor Protocol Number: CQBW276X2201

Sponsor Name: Novartis Pharma AG

Start Date: 2017-07-26

Medical condition: Cystic Fibrosis

Disease:

Version: 20.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Adults

Gender: Male, Female

Trial Protocol: DE (Prematurely Ended), GB (Ongoing)

A randomized, double blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of inhaled QBW276 in patients with cystic fibrosis

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004915-35

Last Update Posted: 04/05/19 07:37AM

Bacteriophage PEV20 and Ciprofloxacin Combination Treatment Enhances Removal of Pseudomonas aeruginosa Biofilm Isolated from Cystic Fibrosis Patients

https://link.springer.com/article/10.1208%2Fs12248-019-0315-0

https://www.ncbi.nlm.nih.gov/pubmed/30949776?dopt=Abstract

Related Articles

Bacteriophage PEV20 and Ciprofloxacin Combination Treatment Enhances Removal of Pseudomonas aeruginosa Biofilm Isolated from Cystic Fibrosis and Wound Patients.

AAPS J. 2019 Apr 04;21(3):49

Authors: Chang RYK, Das T, Manos J, Kutter E, Morales S, Chan HK

Abstract

Antibiotic resistance in Pseudomonas aeruginosa biofilms necessitates the need for novel antimicrobial therapy with anti-biofilm properties. Bacteriophages (phages) are recognized as an ideal biopharmaceutical for combating antibiotic-resistant bacteria especially when used in combination with antibiotics. However, previous studies primarily focused on using phages against of P. aeruginosa biofilms of laboratory strains. In the present study, biofilms of six P. aeruginosa isolated from cystic fibrosis and wound patients, and one laboratory strain was treated singly and with combinations of anti-Pseudomonas phage PEV20 and ciprofloxacin. Of these strains, three were highly susceptible to the phage, while one was partially resistant and one was completely resistant. Combination treatment with PEV20 and ciprofloxacin enhanced biofilm eradication compared with single treatment. Phage and ciprofloxacin synergy was found to depend on phage-resistance profile of the target bacteria. Furthermore, phage and ciprofloxacin combination formulation protected the lung epithelial and fibroblast cells from P. aeruginosa and promoted cell growth. The results demonstrated that thorough screening of phage-resistance is crucial for designing phage-antibiotic formulation. The addition of highly effective phage could reduce the ciprofloxacin concentration required to combat P. aeruginosa infections associated with biofilm in cystic fibrosis and wound patients.

PMID: 30949776 [PubMed – in process]

PubMed:30949776

A Study of AeroVanc for the Treatment of MRSA Infection in CF Patients

https://clinicaltrials.gov/ct2/show/NCT03181932?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F21%2F2019&lupd_d=14

Conditions :   MRSA;   Cystic Fibrosis

Interventions :   Drug: Vancomycin inhalation powder;   Drug: Placebo inhalation powder

Sponsor :   Savara Inc.

Recruiting

A Study of AeroVanc for the Treatment of MRSA Infection in CF Patients

NCT03181932

Fri, 09 Jun 2017 12:00:00 EDT

Last Update Posted: 04/04/19 07:50AM

Effect of Losartan in Cystic Fibrosis (CF)

https://clinicaltrials.gov/ct2/show/NCT03435939?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F21%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Intervention :   Drug: Losartan

Sponsor :   University of Kansas Medical Center

Not yet recruiting

Effect of Losartan in Cystic Fibrosis (CF)-NIH Grant #133240

NCT03435939

Fri, 16 Feb 2018 12:00:00 EST

Last Update Posted: 04/04/19 07:50AM

Safety, Tolerability and Efficacy of S-1226 in Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03903913?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F21%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Intervention :   Drug: S-1226

Sponsor :   SolAeroMed Inc.

Not yet recruiting

Safety, Tolerability and Efficacy of S-1226 in Cystic Fibrosis

NCT03903913

Thu, 04 Apr 2019 12:00:00 EDT

Last Update Posted: 04/04/19 07:50AM

A randomised, multicentre, double-blind, placebo-controlled, crossover trial determining the efficacy of dry powder mannitol in improving lung function in subjects with Cystic Fibrosis aged six to …

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002699-14

EudraCT Number: 2012-002699-14

Sponsor Protocol Number: DPM-CF-204

Sponsor Name: Pharmaxis Ltd.

Start Date: 2013-01-28

Medical condition: Cystic fibrosis in children aged 6 to 17 years

Disease:

Version: 14.1

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Children, Adolescents, Under 18

Gender: Male, Female

Trial Protocol: GB (Ongoing), FR (Completed), BE (Completed), NL (Completed), IT (Completed)

A randomised, multicentre, double-blind, placebo-controlled, crossover trial determining the efficacy of dry powder mannitol in improving lung function in subjects with Cystic Fibrosis aged six to …

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002699-14

Last Update Posted: 04/04/19 05:38AM

A Phase 2, Double-blind, Randomized, Placebo-controlled Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of JBT-101 in Cystic Fibrosis

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002581-23

EudraCT Number: 2015-002581-23

Sponsor Protocol Number: JBT101-CF-001

Sponsor Name: Corbus Pharmaceuticals, Inc.

Start Date: 2015-12-03

Medical condition: Cystic Fibrosis

Cystic Fibrosis is a genetic disorder which results in thick mucus formation on the airways leading to increased lung infections, fibrosis of the lungs and digestive tract and abno…

Disease:

Version: 18.0

SOC Term: 10010331 – Congenital, familial and genetic disorders

Classification Code: 10011762

Term: Cystic fibrosis

Level: PT

Population Age: Adults

Gender: Male, Female

Trial Protocol: BE (Completed), DE (Completed), FR (Completed), GB (Completed)

A Phase 2, Double-blind, Randomized, Placebo-controlled Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of JBT-101 in Cystic Fibrosis

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002581-23

Last Update Posted: 04/03/19 02:45PM

Trial of Inhaled Molgramostim in CF Subjects With NTM Infection

https://clinicaltrials.gov/ct2/show/NCT03597347?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F20%2F2019&lupd_d=14

Conditions :   Mycobacterium Infections, Nontuberculous;   Cystic Fibrosis (CF)

Interventions :   Drug: Molgramostim nebulizer solution;   Device: PARI eFlow nebulizer system

Sponsor :   Savara Inc.

Not yet recruiting

Trial of Inhaled Molgramostim in CF Subjects With NTM Infection

NCT03597347

Tue, 24 Jul 2018 12:00:00 EDT

Last Update Posted: 04/03/19 07:37AM

Cystic Fibrosis Transmembrane Conductance Regulator: A Possible New Target for Photodynamic Therapy Enhances Wound Healing

https://www.liebertpub.com/doi/10.1089/wound.2018.0927

https://www.ncbi.nlm.nih.gov/pubmed/31456905?dopt=Abstract

Related Articles

Cystic Fibrosis Transmembrane Conductance Regulator: A Possible New Target for Photodynamic Therapy Enhances Wound Healing.

Adv Wound Care (New Rochelle). 2019 Oct 01;8(10):476-486

Authors: Chiu WT, Tran TV, Pan SC, Huang HK, Chen YC, Wong TW

Abstract

Objective: Cell migration is an essential process in skin wound healing. Photodynamic therapy (PDT) enhances wound healing by photoactivating a photosensitizer with a specific wavelength of light. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel expressed in multiple layers of keratinocytes. Recent studies showed that the activation of CFTR-related downstream signaling affects skin wound healing. We examined whether indocyanine green (ICG)-mediated PDT-enhanced cell migration is related to CFTR activation. Approach: The spatial and temporal expression levels of CFTR and proteins involved in focal adhesion, including focal adhesion kinase (FAK) and paxillin, were evaluated during cell migration in vitro and in vivo for wound healing. Results: ICG-PDT-conditioned medium collected from cells exposed to 5 J/cm2 near-infrared light in the presence of 100 μg/mL ICG activated CFTR and enhanced HaCaT cell migration. The expression of phosphorylated FAK Tyr861 and phosphorylated paxillin in focal adhesions was spatially and temporally regulated in parallel by ICG-PDT-conditioned medium. Curcumin, a nonspecific activator of CFTR, further increased PDT-enhanced cell migration, whereas inhibition of CFTR and FAK delayed cell migration. The involvement of CFTR in ICG-PDT-enhanced skin wound healing was confirmed in a mouse back skin wound model. Innovation: CFTR is a potential new therapeutic target in ICG-PDT to enhance wound healing. Conclusion: ICG-PDT-enhanced cell migration may be related to activation of the CFTR and FAK pathway. Conditioned medium collected from ICG-PDT may be useful for treating patients with chronic skin ulcer by regulating CFTR expression in keratinocytes.

PMID: 31456905 [PubMed]

PubMed:31456905

Therapeutic Potential of Specialized Pro-resolving Lipid Mediators (SPMs) for the Treatment of Inflammation in Cystic Fibrosis

https://www.frontiersin.org/articles/10.3389/fphar.2019.00252/full

https://www.ncbi.nlm.nih.gov/pubmed/31001110?dopt=Abstract

Related Articles

Roles, Actions, and Therapeutic Potential of Specialized Pro-resolving Lipid Mediators for the Treatment of Inflammation in Cystic Fibrosis.

Front Pharmacol. 2019;10:252

Authors: Recchiuti A, Mattoscio D, Isopi E

Abstract

Non-resolving inflammation is the main mechanism of morbidity and mortality among patients suffering from cystic fibrosis (CF), the most common life-threatening human genetic disease. Resolution of inflammation is an active process timely controlled by endogenous specialized pro-resolving lipid mediators (SPMs) produced locally in inflammatory loci to restrain this innate response, prevent further damages to the host, and permit return to homeostasis. Lipoxins, resolvins, protectins, and maresins are SPM derived from polyunsaturated fatty acids that limit excessive leukocyte infiltration and pro-inflammatory signals, stimulate innate microbial killing, and enhance resolution. Their unique chemical structures, receptors, and bioactions are being elucidated. Accruing data indicate that SPMs carry protective functions against unrelenting inflammation and infections in preclinical models and human CF systems. Here, we reviewed their roles and actions in controlling resolution of inflammation, evidence for their impairment in CF, and proofs of principle for their exploitation as innovative, non-immunosuppressive drugs to address inflammation and infections in CF.

PMID: 31001110 [PubMed]

PubMed:31001110

Safety and efficacy of treatment with lumacaftor in combination with ivacaftor in younger patients with cystic fibrosis

https://www.tandfonline.com/doi/abs/10.1080/17476348.2019.1602040?journalCode=ierx20

https://www.ncbi.nlm.nih.gov/pubmed/30929526?dopt=Abstract

Related Articles

Safety and efficacy of treatment with lumacaftor in combination with ivacaftor in younger patients with cystic fibrosis.

Expert Rev Respir Med. 2019 Mar 30;:

Authors: Cheng PC, Alexiou S, Rubenstein RC

Abstract

INTRODUCTION: Cystic fibrosis (CF) is the most common autosomal recessive disorder affecting approximately 70,000 people worldwide. The lack of functional cystic fibrosis transmembrane conductance regulator (CFTR) causes dysregulation of epithelial fluid transport in the lungs, gastrointestinal tract, and sweat glands. Areas covered: The most common disease-causing CFTR mutation, F508del, is present in nearly 75% of those affected and results in a defective protein. Therapies to improve the function of this mutant protein have the promise to reduce morbidity and mortality in the majority of patients with CF. The combination of lumacaftor, which corrects the aberrant intracellular trafficking of F508del, and ivacaftor, which potentiates CFTR function, is known as OrkambiTM, and is the first drug approved for the treatment of cystic fibrosis (CF) in patients who are homozygous for F508del. OrkambiTM is currently approved for use in children aged 2 and older based on recent data from open-label Phase 3 clinical safety studies. In older patients, treatment with lumacaftor/ivacaftor is associated with a modest, statistically significant improvement in lung function and reduced pulmonary exacerbations in placebo-controlled trials; these findings are also observed in Phase IV observational studies. While severe side effects are rare, chest tightness, elevation of transaminases, and cataracts have been reported and recommendations for monitoring have been established. Expert opinion: OrkambiTM somewhat improves clinical outcomes for people with CF who are homozygous for the F508del mutation, and does so with a reasonable safety profile. This therapy represents a major advance in the therapy for CF, but further advances are needed, perhaps with addition of a third agent to this combination small molecule therapy, in order to expand both the targeted population and beneficial effects.

PMID: 30929526 [PubMed – as supplied by publisher]

PubMed:30929526

Vitamin D inhibits pro-inflammatory cytokines in the airways of cystic fibrosis patients infected by Pseudomonas aeruginosa

https://ijponline.biomedcentral.com/articles/10.1186/s13052-019-0634-x

https://www.ncbi.nlm.nih.gov/pubmed/30922377?dopt=Abstract

Related Articles

Vitamin D inhibits pro-inflammatory cytokines in the airways of cystic fibrosis patients infected by Pseudomonas aeruginosa- pilot study.

Ital J Pediatr. 2019 Mar 29;45(1):41

Authors: Olszowiec-Chlebna M, Koniarek-Maniecka A, Brzozowska A, Błauż A, Rychlik B, Stelmach I

Abstract

BACKGROUND: Vitamin D plays an important role in inflammatory responses after antigen exposure. Interleukin-23 (Il-23) promotes Il-17-dependent inflammation during Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection. We aimed to compare the ability of calcitriol and cholecalciferol to modulate the inflammatory response of the CF airways infected with P. aeruginosa.

METHODS: This was a randomized, placebo-controlled, double-blind, cross-over trial. Twenty-three patients with CF (aged 6-19), chronically infected by P. aeruginosa were randomly assigned to: calcitriol group receiving 1,25(OH)2D 0,5 mcg daily or cholecalciferol group receiving cholecalciferol 1000 IU daily for three months. The levels of Il-23 and Il-17A in the exhaled breath concentrate (EBC) were measured. Calcium-phosphorus balance was also evaluated (serum concentration of calcium, phosphorus, 25OHD, parathormone (PTH) and calcium/creatinine ratio in urine). Data were analyzed using means of Stata/Special Edition, release 14.2. A level of P < 0.05 was considered statistically significant. RESULTS: The level of Il-17A in EBC significantly decreased in calcitriol group from 0,475 pg/mL (± SD 0,515 pg/mL) to 0,384 pg/mL (± SD 0,429 pg/mL) (p = 0,008); there was no change in cholecalciferol group (p = 0,074). The level of Il-23 in EBC did not significantly change in calcitriol group (p = 0,086); there was significant decrease in cholecalciferol group from 8,90 pg/mL (± SD 4,07 pg/mL) to 7,33 pg/mL (± SD 3,88 pg/mL) (p = 0,001). In calcitriol group serum phosphorus and PTH significantly decreased (p = 0,021 and p = 0,019 respectively), the concentration of calcium significantly increased (p = 0,001); there were no changes in cholecalciferol group. CONCLUSIONS: Both analogs of vitamin D revealed their anti-inflammatory effect and reduced the level of Il-17A and Il-23 in the airway of CF patients with chronic P. aeruginosa infection. We observed improvement in calcium-phosphorus metabolism after supplementation with calcitriol, without adverse effects. It is recommended to use vitamin D in CF patients. PMID: 30922377 [PubMed - in process] PubMed:30922377

Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi

https://clinicaltrials.gov/ct2/show/NCT03894657?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F14%2F2019&lupd_d=14

Conditions :   Cystic Fibrosis;   Homozygous F508del Mutation

Interventions :   Diagnostic Test: Nasal brushing;   Other: Sputum sample;   Other: blood sample;   Drug: Orkambi

Sponsor :   Assistance Publique – Hôpitaux de Paris

Not yet recruiting

Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®.

NCT03894657

Thu, 28 Mar 2019 12:00:00 EDT

Last Update Posted: 03/28/19 09:25AM

Prevention of cystic fibrosis: The beginning of the end?

http://stm.sciencemag.org/content/11/485/eaax2361

https://www.ncbi.nlm.nih.gov/pubmed/30918110?dopt=Abstract

Prevention of cystic fibrosis: The beginning of the end?

Sci Transl Med. 2019 Mar 27;11(485):

Authors: Ferkol TW

Abstract

Prenatal and postnatal treatment with a CFTR modifier attenuates pathological changes in a ferret model of cystic fibrosis (Sun et al., this issue).

PMID: 30918110 [PubMed – in process]

PubMed:30918110

In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis

http://stm.sciencemag.org/content/11/485/eaau7531

https://www.ncbi.nlm.nih.gov/pubmed/30918114?dopt=Abstract

Related Articles

In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis.

Sci Transl Med. 2019 Mar 27;11(485):

Authors: Sun X, Yi Y, Yan Z, Rosen BH, Liang B, Winter MC, Evans TIA, Rotti PG, Yang Y, Gray JS, Park SY, Zhou W, Zhang Y, Moll SR, Woody L, Tran DM, Jiang L, Vonk AM, Beekman JM, Negulescu P, Van Goor F, Fiorino DF, Gibson-Corley KN, Engelhardt JF

Abstract

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTR G551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTR G551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.

PMID: 30918114 [PubMed – in process]

PubMed:30918114

Eloxx Pharmaceuticals Presents Positive New Data for Lead Investigational Drug, ELX-02, at the European Cystic Fibrosis Society (ECFS) Basic Science Conference – “We believe these ground-breaking new data establish a solid basis for understanding the activity of ELX-02 and it’s potential for development in the treatment of the high unmet medical need cystic fibrosis patients with nonsense mutations.”

https://www.globenewswire.com/news-release/2019/03/27/1773995/0/en/Eloxx-Pharmaceuticals-Presents-Positive-New-Data-for-Lead-Investigational-Drug-ELX-02-at-the-European-Cystic-Fibrosis-Society-ECFS-Basic-Science-Conference.html

https://apnews.com/Globe%2520Newswire/0477890fdeef1e23fb57e43611e83f77

Plasma membrane-localized TMEM16 proteins are indispensable for expression of CFTR and may therefore have an impact on disease severity in cystic fibrosis

https://link.springer.com/article/10.1007%2Fs00109-019-01770-4

https://www.ncbi.nlm.nih.gov/pubmed/30915480?dopt=Abstract

Related Articles

Plasma membrane-localized TMEM16 proteins are indispensable for expression of CFTR.

J Mol Med (Berl). 2019 Mar 26;:

Authors: Benedetto R, Ousingsawat J, Cabrita I, Pinto M, Lérias JR, Wanitchakool P, Schreiber R, Kunzelmann K

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is the secretory chloride channel in epithelial tissues that has a central role in cystic fibrosis (CF) lung and gastrointestinal disease. A recent publication demonstrates a close association between CFTR and TMEM16A, the calcium-activated chloride channel. Thus, no CFTR chloride currents could be detected in airways and large intestine from mice lacking epithelial expression of TMEM16A. Here, we demonstrate that another plasma membrane-localized TMEM16 paralogue, TMEM16F, can compensate for the lack of TMEM16A. Using TMEM16 knockout mice, human lymphocytes, and a number of human cell lines with endogenous protein expression or heterologous expression, we demonstrate that CFTR can only function in the presence of either TMEM16A or TMEM16F. Double knockout of intestinal epithelial TMEM16A/F expression did not produce offsprings, suggesting a lethal phenotype in utero. Plasma membrane-localized TMEM16A or TMEM16F is required for exocytosis and expression of CFTR in the plasma membrane. TMEM16A/F proteins may therefore have an impact on disease severity in CF. KEY MESSAGES: • Cystic fibrosis is caused by the defective Cl- channel cystic fibrosis transmembrane conductance regulator (CFTR). • A close relationship exists between CFTR and the calcium-activated chloride channels TMEM16A/TMEM16F. • In conditional airway and intestinal knockout mice, lymphocytes from Scott disease patients and in overexpressing cells, CFTR is not functional in the absence of TMEM16A and TMEM16F. • TMEM16A and TMEM16F support membrane exocytosis and are essential for plasma membrane insertion of CFTR.

PMID: 30915480 [PubMed – as supplied by publisher]

PubMed:30915480

Ready to Use Therapeutic Food (RUTF) to Promote Growth in Cystic Fibrosis

https://clinicaltrials.gov/ct2/show/NCT03462056?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F12%2F2019&lupd_d=14

Condition :   Cystic Fibrosis

Intervention :   Dietary Supplement: Cystic Fibrosis Ready to Use Supplemental Food

Sponsors :   Washington University School of Medicine;   Cystic Fibrosis Foundation

Recruiting

Ready to Use Therapeutic Food (RUTF) to Promote Growth in Cystic Fibrosis

NCT03462056

Mon, 12 Mar 2018 12:00:00 EDT

Last Update Posted: 03/26/19 09:41AM

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