https://www.prnewswire.com/news-releases/proteostasis-therapeutics-announces-broad-new-dataset-from-proprietary-combination-and-add-on-cftr-modulator-studies-in-cystic-fibrosis-patients-300817507.html
In Vitro Activity of a Novel Glycopolymer against Biofilms of Burkholderia cepacia Complex Cystic Fibrosis Clinical Isolates – “significant reduction in biofilm thickness was observed following 10-minute treatment of Bcc biofilms”
https://aac.asm.org/content/early/2019/03/19/AAC.00498-19
https://www.ncbi.nlm.nih.gov/pubmed/30910901?dopt=Abstract
Related Articles
In Vitro Activity of a Novel Glycopolymer against Biofilms of Burkholderia cepacia Complex Cystic Fibrosis Clinical Isolates.
Antimicrob Agents Chemother. 2019 Mar 25;:
Authors: Narayanaswamy VP, Duncan AP, LiPuma JJ, Wiesmann WP, Baker SM, Townsend SM
Abstract
Burkholderia cepacia complex (Bcc) lung infections in cystic fibrosis (CF) patients are often associated with a steady decline in lung function and death. The formation of biofilms and inherent multi-drug resistance are virulence factors associated with Bcc infection and contribute to increased risk of mortality in CF patients. New therapeutic strategies targeting bacterial biofilms are anticipated to enhance antibiotic penetration and facilitate resolution of infection. Poly (acetyl, arginyl) glucosamine (PAAG), is a cationic glycopolymer therapeutic being developed to directly target biofilm integrity. In this study, thirteen isolates from 7 species were examined including; B. multivorans, B. cenocepacia, B. gladioli, B. dolosa, B. vietnamiensis, and B. cepacia These isolates were selected for their resistance to standard clinical antibiotics and their ability to form biofilms in vitro. Biofilm biomass was quantitated using static tissue culture plate (TCP) biofilm methods and minimum biofilm eradication concentration (MBEC) assay. Confocal laser scanning microscopy (CLSM) visualized biofilm removal by PAAG during treatment. Both TCP and MBEC methods demonstrated a significant dose-dependent relationship with regard to biofilm removal by 50-200μg/ml PAAG following 1-hour treatment (p<0.01). A significant reduction in biofilm thickness was observed following 10-minute treatment of Bcc biofilms with PAAG compared to vehicle control (p<0.001) in TCP, MBEC, and CLSM analysis. PAAG also rapidly permeabilizes bacteria within the first 10 minutes of treatment. Glycopolymers such as PAAG, are a new class of large-molecule therapeutics that support the treatment of recalcitrant Bcc biofilm. PMID: 30910901 [PubMed - as supplied by publisher] PubMed:30910901
Study to Evaluate the Safety & Tolerability of MRT5005 Administered by Nebulization in Adults With Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT03375047?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F07%2F2019&lupd_d=14
Condition : Cystic Fibrosis
Interventions : Drug: MRT5005; Drug: Normal saline
Sponsor : Translate Bio, Inc.
Recruiting
Study to Evaluate the Safety & Tolerability of MRT5005 Administered by Nebulization in Adults With Cystic Fibrosis
NCT03375047
Fri, 15 Dec 2017 12:00:00 EST
Last Update Posted: 03/21/19 09:54AM
Brevenal, a Marine Natural Product, is Anti-Inflammatory and an Immunomodulator of Macrophage and Lung Epithelial Cells
https://www.mdpi.com/1660-3397/17/3/184/htm
https://www.ncbi.nlm.nih.gov/pubmed/30897777?dopt=Abstract
Related Articles
Brevenal, a Marine Natural Product, is Anti-Inflammatory and an Immunomodulator of Macrophage and Lung Epithelial Cells.
Mar Drugs. 2019 Mar 20;17(3):
Authors: Keeler DM, Grandal MK, McCall JR
Abstract
Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are some of the leading causes of illness and fatalities worldwide. The search for novel treatments led to the exploration of marine natural products as drug candidates to combat the debilitating effects of mucus accumulation and chronic inflammation. Previous research showed that an alga-derived compound, brevenal, could attenuate the effects of inflammatory agents, but the mechanisms by which it exerted its effects remained unclear. We investigated the effects of brevenal on lipopolysaccharide (LPS) induced cytokine/chemokine production from murine macrophages and human lung epithelial cells. It was found that brevenal reduces proinflammatory mediator secretion while preserving anti-inflammatory secretion from these cells. Furthermore, we found that brevenal does not alter cell surface Toll-like receptor 4 (TLR4) expression, thereby maintaining the cells’ ability to respond to bacterial infection. However, brevenal does alter macrophage activation states, as demonstrated by reduced expression of both M1 and M2 phenotype markers, indicating this putative anti-inflammatory drug shifts innate immune cells to a less active state. Such a mechanism of action would be ideal for reducing inflammation in the lung, especially with patients suffering from chronic respiratory diseases, where inflammation can be lethal.
PMID: 30897777 [PubMed – in process]
PubMed:30897777
Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells – “could represent a novel site of therapeutic intervention to address inflammation in CF”
https://www.physiology.org/doi/abs/10.1152/ajplung.00369.2018
https://www.ncbi.nlm.nih.gov/pubmed/30892081?dopt=Abstract
Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells.
Am J Physiol Lung Cell Mol Physiol. 2019 Mar 20;:
Authors: Rymut SM, Lu B, Perez A, Corey DA, Lamb K, Cotton CU, Kelley TJ
Abstract
The use of high-dose ibuprofen as an anti-inflammatory therapy in cystic fibrosis has been shown to be an effective intervention though use is limited due to potential adverse events. Identifying the mechanism of ibuprofen efficacy would aid in the development of new therapies that avoid these adverse events. Previous findings demonstrated that ibuprofen treatment restores the regulation of microtubule dynamics in cystic fibrosis (CF) epithelial cells through a 5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent mechanism. The goal of this study is to define the AMPK pathway that leads to microtubule regulation. Here, it is identified that inhibition of acetyl-CoA carboxylase (ACC) is the key step in mediating the AMPK effect. ACC inhibition with 5-(Tetradecyloxy)-2-furoic acid (TOFA) increases microtubule reformation rates in cultured and primary CF epithelial cells to WT rates. TOFA treatment also restores microtubule dependent distribution of cholesterol and Rab7-positive organelles, as well as reduces expression of the pro-inflammatory signaling molecule RhoA to WT levels. ACC activation with citrate replicates these CF phenotypes in WT cells further supporting the role of AMPK signaling through ACC as a key mediator in CF cell signaling. It is concluded that ACC inhibition is the key step in the efficacy of AMPK activation at the cellular level and could represent a novel site of therapeutic intervention to address inflammation in CF.
PMID: 30892081 [PubMed – as supplied by publisher]
PubMed:30892081
New method catches cystic fibrosis inflammatory enzyme in the act
https://cen.acs.org/analytical-chemistry/diagnostics/New-method-catches-cystic-fibrosis/97/web/2019/03
Cell-Selective Regulation of CFTR Gene Expression: Relevance to Gene Editing Therapeutics
https://www.mdpi.com/2073-4425/10/3/235
https://www.ncbi.nlm.nih.gov/pubmed/30893953?dopt=Abstract
Related Articles
Cell-Selective Regulation of CFTR Gene Expression: Relevance to Gene Editing Therapeutics.
Genes (Basel). 2019 Mar 19;10(3):
Authors: Swahn H, Harris A
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) gene is an attractive target for gene editing approaches, which may yield novel therapeutic approaches for genetic diseases such as cystic fibrosis (CF). However, for gene editing to be effective, aspects of the three-dimensional (3D) structure and cis-regulatory elements governing the dynamic expression of CFTR need to be considered. In this review, we focus on the higher order chromatin organization required for normal CFTR locus function, together with the complex mechanisms controlling expression of the gene in different cell types impaired by CF pathology. Across all cells, the CFTR locus is organized into an invariant topologically associated domain (TAD) established by the architectural proteins CCCTC-binding factor (CTCF) and cohesin complex. Additional insulator elements within the TAD also recruit these factors. Although the CFTR promoter is required for basal levels of expression, cis-regulatory elements (CREs) in intergenic and intronic regions are crucial for cell-specific and temporal coordination of CFTR transcription. These CREs are recruited to the promoter through chromatin looping mechanisms and enhance cell-type-specific expression. These features of the CFTR locus should be considered when designing gene-editing approaches, since failure to recognize their importance may disrupt gene expression and reduce the efficacy of therapies.
PMID: 30893953 [PubMed]
PubMed:30893953
An Efficacy and Safety Study of SPX-101 Inhalation Solution in Subjects With Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT03229252?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=03%2F05%2F2019&lupd_d=14
Condition : Cystic Fibrosis
Interventions : Drug: Placebo Inhalation Solution; Drug: SPX-101
Sponsor : Spyryx Biosciences, Inc.
Recruiting
An Efficacy and Safety Study of SPX-101 Inhalation Solution in Subjects With Cystic Fibrosis
NCT03229252
Tue, 25 Jul 2017 12:00:00 EDT
Last Update Posted: 03/19/19 09:26AM
Choline Supplementation in Cystic Fibrosis – The Metabolic and Clinical Impact
https://www.mdpi.com/2072-6643/11/3/656
https://www.ncbi.nlm.nih.gov/pubmed/30889905?dopt=Abstract
Related Articles
Choline Supplementation in Cystic Fibrosis-The Metabolic and Clinical Impact.
Nutrients. 2019 Mar 18;11(3):
Authors: Bernhard W, Lange R, Graepler-Mainka U, Engel C, Machann J, Hund V, Shunova A, Hector A, Riethmüller J
Abstract
BACKGROUND: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat.
METHODS: 10 adult male CF patients were recruited (11/2014⁻1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84⁻91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D₉]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis.
RESULTS: Supplementation increased plasma choline from 4.8 (4.1⁻6.2) µmol/L to 10.5 (8.5⁻15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D₉-labeled PC was decreased (12.2 [10.5⁻18.3] µmol/L vs. 17.7 [15.5⁻22.4] µmol/L, p < 0.01), indicating D₉-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9⁻74.8)% to 78.3 (60.1⁻83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37⁻8.82)% to 0.84 (0.56⁻1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h. CONCLUSIONS: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials. PMID: 30889905 [PubMed - in process] PubMed:30889905
Two UIs work together on cystic fibrosis breakthrough
https://www.press-citizen.com/story/news/2019/03/18/new-reserach-limiting-infection-cystic-fibrosis-patients/3161934002/
Aerosolized agents for airway clearance in cystic fibrosis
https://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.24306
https://www.ncbi.nlm.nih.gov/pubmed/30884217?dopt=Abstract
Aerosolized agents for airway clearance in cystic fibrosis.
Pediatr Pulmonol. 2019 Mar 18;:
Authors: Southern KW, Clancy JP, Ranganathan S
Abstract
The outlook for people with cystic fibrosis (CF) has improved considerably as a result of conventional therapies including aerosolized agents for airway clearance. These will continue to play a significant role in maintaining well-being and improving survival, even as newer agents emerge that correct the underlying CF defect. In this review, we explore the evidence supporting the use of dornase alfa, hypertonic saline, and mannitol in improving mucus clearance in patients with CF from different age groups with differing disease severity. We also discuss the clinical use of these agents in the context of available international guidelines as well as practical considerations in the clinic, highlighting the importance of a multidisciplinary approach and shared decision-making. Unanswered questions regarding the optimal use of these agents are highlighted.
PMID: 30884217 [PubMed – as supplied by publisher]
PubMed:30884217
Autophagy suppresses the pathogenic immune response to dietary antigens in cystic fibrosis – “autophagy stimulation may mitigate the intestinal malfunction of CF patients”
https://www.nature.com/articles/s41419-019-1500-x
https://www.ncbi.nlm.nih.gov/pubmed/30874543?dopt=Abstract
Autophagy suppresses the pathogenic immune response to dietary antigens in cystic fibrosis.
Cell Death Dis. 2019 Mar 15;10(4):258
Authors: Villella VR, Esposito S, Ferrari E, Monzani R, Tosco A, Rossin F, Castaldo A, Silano M, Marseglia GL, Romani L, Barlev NA, Piacentini M, Raia V, Kroemer G, Maiuri L
Abstract
Under physiological conditions, a finely tuned system of cellular adaptation allows the intestinal mucosa to maintain the gut barrier function while avoiding excessive immune responses to non-self-antigens from dietary origin or from commensal microbes. This homeostatic function is compromised in cystic fibrosis (CF) due to loss-of-function mutations in the CF transmembrane conductance regulator (CFTR). Recently, we reported that mice bearing defective CFTR are abnormally susceptible to a celiac disease-like enteropathy, in thus far that oral challenge with the gluten derivative gliadin elicits an inflammatory response. However, the mechanisms through which CFTR malfunction drives such an exaggerated response to dietary protein remains elusive. Here we demonstrate that the proteostasis regulator/transglutaminase 2 (TGM2) inhibitor cysteamine restores reduced Beclin 1 (BECN1) protein levels in mice bearing cysteamine-rescuable F508del-CFTR mutant, either in homozygosis or in compound heterozygosis with a null allele, but not in knock-out CFTR mice. When cysteamine restored BECN1 expression, autophagy was increased and gliadin-induced inflammation was reduced. The beneficial effects of cysteamine on F508del-CFTR mice were lost when these mice were backcrossed into a Becn1 haploinsufficient/autophagy-deficient background. Conversely, the transfection-enforced expression of BECN1 in human intestinal epithelial Caco-2 cells mitigated the pro-inflammatory cellular stress response elicited by the gliadin-derived P31-43 peptide. In conclusion, our data provide the proof-of-concept that autophagy stimulation may mitigate the intestinal malfunction of CF patients.
PMID: 30874543 [PubMed – in process]
PubMed:30874543
Cystic fibrosis transmembrane conductance regulator modulators: Present and future in cystic fibrosis treatment
https://www.ncbi.nlm.nih.gov/pubmed/30869491?dopt=Abstract
Cystic fibrosis transmembrane conductance regulator modulators: Present and future in cystic fibrosis treatment. A review.
Arch Argent Pediatr. 2019 Apr 01;117(2):e131-e136
Authors: De la Hoz D, Villamil Osorio M, Restrepo-Gualteros SM
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are the present and future of drug management for patients with cystic fibrosis. The objective of this article is to review this therapeutic option. Scientific articles were reviewed by searching the MedLine database, which is available through the Cystic Fibrosis Foundation’s official website, from 2009 to 2018, in English. Twelve articles about the current status of research in CFTR modulators were selected without restrictions regarding the type of study. To date, the United States Food and Drug Administration has approved three modulators: ivacaftor, lumacaftor + ivacaftor, and tezacaftor + ivacaftor, while other 11 drugs are being studied in different investigation phases. CFTR modulator therapy is a developing reality aimed at the highest goal of personalized medicine and promises to improve the quality of life of cystic fibrosis patients.
PMID: 30869491 [PubMed – in process]
PubMed:30869491
New University of Illinois Research Points To Possible Cystic Fibrosis Treatment – Interview with Professor Martin Burke
https://will.illinois.edu/news/story/new-u-of-i-research-points-to-possible-cystic-fibrosis-treatment
Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease
https://www.mdpi.com/2073-4425/10/3/218
https://www.ncbi.nlm.nih.gov/pubmed/30875857?dopt=Abstract
Related Articles
Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease.
Genes (Basel). 2019 Mar 14;10(3):
Authors: Marquez Loza LI, Yuen EC, McCray PB
Abstract
Despite the continued development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs for the treatment of cystic fibrosis (CF), the need for mutation agnostic treatments remains. In a sub-group of CF individuals with mutations that may not respond to modulators, such as those with nonsense mutations, CFTR gene transfer to airway epithelia offers the potential for an effective treatment. Lentiviral vectors are well-suited for this purpose because they transduce nondividing cells, and provide long-term transgene expression. Studies in primary cultures of human CF airway epithelia and CF animal models demonstrate the long-term correction of CF phenotypes and low immunogenicity using lentiviral vectors. Further development of CF gene therapy requires the investigation of optimal CFTR expression in the airways. Lentiviral vectors with improved safety features have minimized insertional mutagenesis safety concerns raised in early clinical trials for severe combined immunodeficiency using γ-retroviral vectors. Recent clinical trials using improved lentiviral vectors support the feasibility and safety of lentiviral gene therapy for monogenetic diseases. While work remains to be done before CF gene therapy reaches the bedside, recent advances in lentiviral vector development reviewed here are encouraging and suggest it could be tested in clinical studies in the near future.
PMID: 30875857 [PubMed]
PubMed:30875857
A Practical Review of Proteasome Pharmacology – proteasome function a target for future therapeutic intervention in cystic fibrosis
http://pharmrev.aspetjournals.org/content/71/2/170
https://www.ncbi.nlm.nih.gov/pubmed/30867233?dopt=Abstract
Related Articles
A Practical Review of Proteasome Pharmacology.
Pharmacol Rev. 2019 Apr;71(2):170-197
Authors: Thibaudeau TA, Smith DM
Abstract
The ubiquitin proteasome system (UPS) degrades individual proteins in a highly regulated fashion and is responsible for the degradation of misfolded, damaged, or unneeded cellular proteins. During the past 20 years, investigators have established a critical role for the UPS in essentially every cellular process, including cell cycle progression, transcriptional regulation, genome integrity, apoptosis, immune responses, and neuronal plasticity. At the center of the UPS is the proteasome, a large and complex molecular machine containing a multicatalytic protease complex. When the efficiency of this proteostasis system is perturbed, misfolded and damaged protein aggregates can accumulate to toxic levels and cause neuronal dysfunction, which may underlie many neurodegenerative diseases. In addition, many cancers rely on robust proteasome activity for degrading tumor suppressors and cell cycle checkpoint inhibitors necessary for rapid cell division. Thus, proteasome inhibitors have proven clinically useful to treat some types of cancer, especially multiple myeloma. Numerous cellular processes rely on finely tuned proteasome function, making it a crucial target for future therapeutic intervention in many diseases, including neurodegenerative diseases, cystic fibrosis, atherosclerosis, autoimmune diseases, diabetes, and cancer. In this review, we discuss the structure and function of the proteasome, the mechanisms of action of different proteasome inhibitors, various techniques to evaluate proteasome function in vitro and in vivo, proteasome inhibitors in preclinical and clinical development, and the feasibility for pharmacological activation of the proteasome to potentially treat neurodegenerative disease.
PMID: 30867233 [PubMed – in process]
PubMed:30867233
Amphotericin B improves cystic fibrosis symptoms in cultured cells and pigs
https://cen.acs.org/biological-chemistry/Amphotericin-B-improves-cystic-fibrosis/97/i11
Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia
https://www.nature.com/articles/s41586-019-1018-5
Antifungal drug could help cystic fibrosis patients for whom common treatments don’t work
https://www.sciencemag.org/news/2019/03/antifungal-drug-could-help-cystic-fibrosis-patients-whom-common-treatments-don-t-work
Pore-forming small molecules offer a promising way to tackle cystic fibrosis
https://www.nature.com/articles/d41586-019-00781-y
Clinical validation of an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy through a prospective interventional study in paediatric patients with Cystic Fibrosis
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213216
https://www.ncbi.nlm.nih.gov/pubmed/30861039?dopt=Abstract
Clinical validation of an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy through a prospective interventional study in paediatric patients with Cystic Fibrosis.
PLoS One. 2019;14(3):e0213216
Authors: Calvo-Lerma J, Hulst J, Boon M, Colombo C, Masip E, Ruperto M, Fornés-Ferrer V, van der Wiel E, Claes I, Garriga M, Roca M, Crespo-Escobar P, Bulfamante A, Woodcock S, Martínez-Barona S, Andrés A, de Boeck K, Ribes-Koninckx C, MyCyFAPP project
Abstract
BACKGROUND: A method to adjust Pancreatic Enzyme Replacement Therapy in Cystic Fibrosis is not currently available.
OBJECTIVES: To assess the in vivo efficacy of a method to adjust the dose of enzymatic supplement in CF extrapolated from previous in vitro digestion studies (theoretical optimal dose, TOD). Secondly, to assess how individual patient characteristics influence the expected coefficient of fat absorption (CFA) and thus to identify an individual correction factor to improve TOD.
METHODS: A prospective interventional study in 43 paediatric patients with CF from 5 European centres. They followed a 24h fixed diet with the theoretical optimal dose for each meal. Faecal collection was carried out between colorimetric markers in order to include all the faeces corresponding to the fixed diet. Beta regression models were applied to assess the associations of individual patient characteristics with the CFA.
RESULTS: Median CFA was 90% (84, 94% 1st, 3rd Q.) with no significant differences among centres. Intestinal transit time was positively associated with CFA (p = 0.007), but no statistical associations were found with and age, gender, phenotype or BMI. Regression model showed no improvement of the in vitro predicted theoretical optimal dose when taking individual patient characteristics into account.
CONCLUSION: Strict adherence to the theoretical optimal dose of enzymatic supplement for a prescribed meal, led to median CFA levels at the clinical target of 90% with a low variability between patients. The proposed method can be considered as a first approach for an evidence-based method in PERT dosing based on food characteristics. Results have to be confirmed in free dietary settings.
PMID: 30861039 [PubMed – in process]
PubMed:30861039
Biochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain
https://www.sciencedirect.com/science/article/pii/S0163782719300116?via%3Dihub
https://www.ncbi.nlm.nih.gov/pubmed/30876862?dopt=Abstract
Related Articles
Biochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain.
Prog Lipid Res. 2019 Mar 12;:
Authors: Garić D, De Sanctis JB, Shah J, Dumut DC, Radzioch D
Abstract
Ceramides, the principal building blocks of all sphingolipids, have attracted the attention of many scientists around the world interested in developing treatments for cystic fibrosis, the most common genetic disease of Caucasians. Many years of fruitful research in this field have produced some fundamentally important, yet controversial results. Here, we aimed to summarize the current knowledge on the role of long- and very-long- chain ceramides, the most abundant species of ceramides in animal cells, in cystic fibrosis and other diseases. We also aim to explain the importance of the length of their side chain in the context of stability of transmembrane proteins through a concise synthesis of their biophysical chemistry, cell biology, and physiology. This review also addresses several remaining riddles in this field. Finally, we discuss the technical challenges associated with the analysis and quantification of ceramides. We provide the evaluation of the antibodies used for ceramide quantification and we demonstrate their lack of specificity. Results and discussion presented here will be of interest to anyone studying these enigmatic lipids.
PMID: 30876862 [PubMed – as supplied by publisher]
PubMed:30876862
The Effect of PC945 on Aspergillus Fumigatus Lung Infection in Patients With Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT03870841?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=02%2F26%2F2019&lupd_d=14
Conditions : Aspergillosis; Cystic Fibrosis
Intervention : Drug: PC945
Sponsor : Pulmocide Ltd
Not yet recruiting
The Effect of PC945 on Aspergillus Fumigatus Lung Infection in Patients With Cystic Fibrosis
NCT03870841
Tue, 12 Mar 2019 12:00:00 EDT
Last Update Posted: 03/12/19 09:59AM
Two CFTR mutations within codon 970 differently impact on the chloride channel functionality
https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23741
https://www.ncbi.nlm.nih.gov/pubmed/30851139?dopt=Abstract
Two CFTR mutations within codon 970 differently impact on the chloride channel functionality.
Hum Mutat. 2019 Mar 09;:
Authors: Amato F, Scudieri P, Musante I, Tomati V, Caci E, Comegna M, Maietta S, Manzoni F, di Lullo AM, De Wachter E, Vanderhelst E, Terlizzi V, Braggion C, Castaldo G, Galietta LJV
Abstract
Pharmacological rescue of mutant CFTR in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By cDNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of mRNA from patients cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level in order to determine if the pharmacotherapy of CFTR basic defect is appropriate. This article is protected by copyright. All rights reserved.
PMID: 30851139 [PubMed – as supplied by publisher]
PubMed:30851139
Cystic Fibrosis Plasma Blunts the Immune Response to Bacterial Infection
https://www.atsjournals.org/doi/10.1165/rcmb.2018-0114OC
https://www.ncbi.nlm.nih.gov/pubmed/30848661?dopt=Abstract
Cystic Fibrosis Plasma Blunts the Immune Response to Bacterial Infection.
Am J Respir Cell Mol Biol. 2019 Mar 08;:
Authors: Zhang X, Pan A, Jia S, Ideozu JE, Woods K, Murkowski K, Hessner MJ, Simpson PM, Levy H
Abstract
RATIONALE: Cystic fibrosis (CF) is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). It remains unclear whether the abnormal immune response in CF involves extrinsic signals released from the external or internal environment.
OBJECTIVES: To characterize the peripheral immune signatures in CF and its association with clinical phenotypes.
METHODS: Healthy peripheral blood mononuclear cells (PBMCs) were cultured with plasma from CF probands (CF) or healthy controls (HC) followed by nCounter gene and microRNA (miRNA) profiling. A discovery cohort of 12 CF and 12 HC and a validation cohort of 103 CF and 31 HC (our previous microarray data, GSE71799) were analyzed to characterize the composition of cultured immune cells and establish a miRNA‒mRNA network. Cell compositions and miRNA profiles were associated with clinical characteristics of the cohorts.
MEASUREMENTS AND MAIN RESULTS: Significantly differentially expressed genes and abundance of myeloid cells were downregulated in PMBCs after culture with CF plasma (p < 0.05). Top-ranked miRNAs that increased in response to CF plasma (adjusted p < 0.05) included miR-155 and miR-146a, which target many immune-related genes such as IL-8. Pseudomonas aeruginosa infection was negatively associated with abundance of monocytes and the presence of those regulatory miRNAs. CONCLUSIONS: Extrinsic signals in plasma from CF patients led to monocyte inactivation and miRNA upregulation in PBMC. An improved understanding of the immune effects of extrinsic factors in CF holds great promise for integrating immunomodulatory cell therapies into current treatment strategies in CF. PMID: 30848661 [PubMed - as supplied by publisher] PubMed:30848661
SMAD Signaling Restricts Mucous Cell Differentiation In Human Airway Epithelium
https://www.atsjournals.org/doi/10.1165/rcmb.2018-0326OC
https://www.ncbi.nlm.nih.gov/pubmed/30848657?dopt=Abstract
SMAD Signaling Restricts Mucous Cell Differentiation In Human Airway Epithelium.
Am J Respir Cell Mol Biol. 2019 Mar 08;:
Authors: Feldman MB, Wood M, Lapey A, Mou H
Abstract
Mucin-secreting goblet cell metaplasia and hyperplasia (GCMH) is a common pathological phenotype in many human respiratory diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, primary ciliary dyskinesia, and infections. A better understanding of how goblet cell quantities or proportions in the airway epithelium are regulated may provide novel therapeutic targets to mitigate GCMH in these devastating diseases. We identify canonical SMAD signaling as the principle pathway restricting goblet cell differentiation in human airway epithelium. Differentiated goblet cells express low levels of phosphorylated SMAD. Accordingly, inhibition of SMAD signaling markedly amplifies GCMH induced by mucous mediators. In contrast, SMAD signaling activation impedes goblet cell generation and accelerates the resolution of preexisting GCMH. SMAD signaling inhibition can override the suppressive effects imposed by a GABAergic receptor inhibitor, suggesting the GABAergic pathway likely operates through inhibition of SMAD signaling in regulating mucous differentiation. Collectively, our data demonstrate that SMAD signaling plays a determining role in mucous cell differentiation and thus raises the possibility that dysregulation of this pathway contributes to respiratory pathophysiology during airway inflammation and pulmonary diseases. Additionally, our study also highlights the potential for SMAD modulation as a therapeutic target in mitigating GCMH.
PMID: 30848657 [PubMed – as supplied by publisher]
PubMed:30848657
The effects of cycled inhaled aztreonam on the cystic fibrosis (CF) lung microbiome
https://linkinghub.elsevier.com/retrieve/pii/S1569199319300281
https://www.ncbi.nlm.nih.gov/pubmed/30857926?dopt=Abstract
Related Articles
The effects of cycled inhaled aztreonam on the cystic fibrosis (CF) lung microbiome.
J Cyst Fibros. 2019 Mar 08;:
Authors: Heirali AA, Acosta N, Storey DG, Workentine ML, Somayaji R, Laforest-Lapointe I, Leung W, Quon BS, Berthiaume Y, Rabin HR, Waddell BJ, Rossi L, Surette MG, Parkins MD
Abstract
BACKGROUND: To improve clinical outcomes, cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infections are prescribed inhaled anti-pseudomonal antibiotics. Although, a diverse microbial community exists within CF airways, little is known about how the CF microbiota influences patient outcomes. We hypothesized that organisms within the CF microbiota are affected by inhaled-antibiotics and baseline microbiome may be used to predict therapeutic response.
METHODS: Adults with chronic P. aeruginosa infection from four clinics were observed during a single 28-day on/off inhaled-aztreonam cycle. Patients performed serial sputum collection, CF-respiratory infection symptom scores (CRISS), and spirometry. Patients achieving a decrease of ≥2 CRISS by day 28 were categorized as subjective responders (SR). The airway microbiome was defined by Illumina MiSeq analysis of the 16S rRNA gene.
RESULTS: Thirty-seven patients (median 37.4 years and FEV1 44% predicted) were enrolled. No significant cohort-wide changes in the microbiome were observed between on/off AZLI cycles in either alpha- or beta-diversity metrics. However, at an individual level shifts were apparent. Twenty-one patients (57%) were SR and fourteen patients did not subjectively respond. While alpha-diversity metrics did not associate with response, patients who did not subjectively respond had a higher abundance of Staphylococcus and Streptococcus, and lower abundance of Haemophilus.
CONCLUSIONS: The CF microbiome is relatively resilient to AZLI perturbations. However, associated changes were observed at the individual patient level. The relative abundance of key “off-target” organisms associated with subjective improvements suggesting that the microbiome may be used as a tool to predict patient response – potentially improving outcomes.
PMID: 30857926 [PubMed – as supplied by publisher]
PubMed:30857926
A Phase 1/2a Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of IONIS-ENaCRx in Patients With Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT03647228?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=02%2F22%2F2019&lupd_d=14
Condition : Healthy Subjects
Interventions : Drug: IONIS-ENaCRx; Drug: Placebo
Sponsor : Ionis Pharmaceuticals, Inc.
Recruiting
A Phase 1/2a Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of IONIS-ENaCRx in Healthy Volunteers and Patients With Cystic Fibrosis
NCT03647228
Mon, 27 Aug 2018 12:00:00 EDT
Last Update Posted: 03/08/19 11:56AM
Vertex’s cystic fibrosis therapy meets goal of late-stage studies
https://uk.reuters.com/article/vertex-pharms-study/vertexs-cystic-fibrosis-therapy-meets-goal-of-late-stage-studies-idUKL3N20S4CR
Vertex cystic fibrosis triple combo therapy succeeds in important trials
https://www.reuters.com/article/us-vertex-pharms-study/vertex-cystic-fibrosis-triple-combo-therapy-succeeds-in-important-trials-idUSKCN1QN1LI
Pyruvate-depleting conditions induce biofilm dispersion and enhance the efficacy of antibiotics in killing biofilms in vitro and in vivo
https://www.nature.com/articles/s41598-019-40378-z
https://www.ncbi.nlm.nih.gov/pubmed/30842579?dopt=Abstract
Related Articles
Pyruvate-depleting conditions induce biofilm dispersion and enhance the efficacy of antibiotics in killing biofilms in vitro and in vivo.
Sci Rep. 2019 Mar 06;9(1):3763
Authors: Goodwine J, Gil J, Doiron A, Valdes J, Solis M, Higa A, Davis S, Sauer K
Abstract
The formation of biofilms is a developmental process initiated by planktonic cells transitioning to the surface, which comes full circle when cells disperse from the biofilm and transition to the planktonic mode of growth. Considering that pyruvate has been previously demonstrated to be required for the formation of P. aeruginosa biofilms, we asked whether pyruvate likewise contributes to the maintenance of the biofilm structure, with depletion of pyruvate resulting in dispersion. Here, we demonstrate that the enzymatic depletion of pyruvate coincided with the dispersion of established biofilms by S. aureus and laboratory and clinical P. aeruginosa isolates. The dispersion response was dependent on pyruvate fermentation pathway components but independent of proteins previously described to contribute to P. aeruginosa biofilm dispersion. Using porcine second-degree burn wounds infected with P. aeruginosa biofilm cells, we furthermore demonstrated that pyruvate depletion resulted in a reduction of biofilm biomass in vivo. Pyruvate-depleting conditions enhanced the efficacy of tobramycin killing of the resident wound biofilms by up to 5-logs. Our findings strongly suggest the management of pyruvate availability to be a promising strategy to combat biofilm-related infections by two principal pathogens associated with wound and cystic fibrosis lung infections.
PMID: 30842579 [PubMed – in process]
PubMed:30842579
Nonsense Mediated RNA Decay Pathway Inhibition Restores Expression and Function of W1282X CFTR
https://www.atsjournals.org/doi/10.1165/rcmb.2018-0316OC
https://www.ncbi.nlm.nih.gov/pubmed/30836009?dopt=Abstract
Nonsense Mediated RNA Decay Pathway Inhibition Restores Expression and Function of W1282X CFTR.
Am J Respir Cell Mol Biol. 2019 Mar 05;:
Authors: Keenan MM, Huang L, Jordan NJ, Wong E, Cheng Y, Valley HC, Mahiou J, Liang F, Bihler H, Mense M, Guo S, Monia BP
Abstract
RATIONALE: The recessive genetic disease cystic fibrosis is caused by loss of function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 10% of cystic fibrosis patients have at least one allele with a nonsense mutation in CFTR. Nonsense mutations generate premature termination codons that can subject mRNA transcripts to rapid degradation through the nonsense mediated mRNA decay (NMD) pathway. Currently, there are no approved therapies specifically targeting nonsense mutations in CFTR.
OBJECTIVES: Here, we identify antisense oligonucleotides (ASOs) targeting the nonsense mediated decay factor SMG1 to inhibit the NMD pathway and determine their effects on the W1282X CFTR mutation.
METHODS: First, we develop and validate two in vitro models of the W1282X CFTR mutation. Next, we treat these cells with antisense oligonucleotides to inhibit nonsense mediated decay and measure the effects of these treatments on W1282X expression and function.
MEASUREMENTS AND MAIN RESULTS: SMG1-ASO mediated NMD inhibition upregulates the RNA, protein and surface-localized protein expression of the truncated W1282X gene product. Additionally, these ASOs increase the CFTR chloride channel function in cells homozygous for the W1282X mutation.
CONCLUSIONS: Our approach suggests a new therapeutic strategy for patients harboring nonsense mutations and may be beneficial as a single agent in CF patients with the W1282X mutation.
PMID: 30836009 [PubMed – as supplied by publisher]
PubMed:30836009
Window of opportunity for treatment of early cystic fibrosis lung infections
https://www.sciencedaily.com/releases/2019/03/190304121505.htm
European HIT-CF Project to Explore ELX-02 as Treatment for Rare CF Mutations
Small molecule-facilitated anion transporters in cells for a novel cystic fibrosis therapeutic approach
https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14649
https://www.ncbi.nlm.nih.gov/pubmed/30825185?dopt=Abstract
Related Articles
Small molecule-facilitated anion transporters in cells for a novel cystic fibrosis therapeutic approach.
Br J Pharmacol. 2019 Mar 01;:
Authors: Fiore M, Cossu C, Capurro V, Picco C, Ludovico A, Mielczarek M, Carreira-Barral I, Caci E, Baroni D, Quesada R, Moran O
Abstract
BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CFTR protein, a cAMP-dependent anion channel involved in fluid transport across epithelium. Due to their capability to replace the ion transport independently from the genetic mutation that affects the CFTR, small synthetic transmembrane anion transporters, named anionophores, are candidates as new potential CF therapeutics.
EXPERIMENTAL APPROACH: With the aim of evaluating their impact on cell physiology, we have analysed the transport properties of five compounds, three prodigiosines and two tambjamines.
KEY RESULTS: All studied compounds are capable of transporting halides and bicarbonate across the cell membrane, with a higher transport capacity at acidic pH. Interestingly, the presence of these anionophores do not interfere with the activation of CFTR, and do not modify the action of the lumacaftor and ivacaftor, a CFTR-corrector and -potentiator, respectively.
CONCLUSION AND IMPLICATIONS: Their ability to transport chloride and bicarbonate when applied at low concentration take shape as a promising starting point for the development of novel CF-therapy drug candidates.
PMID: 30825185 [PubMed – as supplied by publisher]
PubMed:30825185
A Study to Evaluate the Safety and Efficacy of Long-term Treatment With TEZ/IVA in CF Subjects With an F508del CFTR Mutation
https://clinicaltrials.gov/ct2/show/NCT03537651?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=02%2F15%2F2019&lupd_d=14
Condition : Cystic Fibrosis
Interventions : Drug: TEZ; Drug: IVA
Sponsor : Vertex Pharmaceuticals Incorporated
Active, not recruiting
A Study to Evaluate the Safety and Efficacy of Long-term Treatment With TEZ/IVA in CF Subjects With an F508del CFTR Mutation
NCT03537651
Fri, 25 May 2018 12:00:00 EDT
Last Update Posted: 03/01/19 05:18PM
Emerging Therapeutic Approaches for Cystic Fibrosis – From Gene Editing to Personalized Medicine
https://www.frontiersin.org/articles/10.3389/fphar.2019.00121/full
https://www.ncbi.nlm.nih.gov/pubmed/30873022?dopt=Abstract
Related Articles
Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine.
Front Pharmacol. 2019;10:121
Authors: Pranke I, Golec A, Hinzpeter A, Edelman A, Sermet-Gaudelus I
Abstract
An improved understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein structure and the consequences of CFTR gene mutations have allowed the development of novel therapies targeting specific defects underlying CF. Some strategies are mutation specific and have already reached clinical development; some strategies include a read-through of the specific premature termination codons (read-through therapies, nonsense mediated decay pathway inhibitors for Class I mutations); correction of CFTR folding and trafficking to the apical plasma membrane (correctors for Class II mutations); and an increase in the function of CFTR channel (potentiators therapy for Class III mutations and any mutant with a residual function located at the membrane). Other therapies that are in preclinical development are not mutation specific and include gene therapy to edit the genome and stem cell therapy to repair the airway tissue. These strategies that are directed at the basic CF defects are now revolutionizing the treatment for patients and should positively impact their survival rates.
PMID: 30873022 [PubMed]
PubMed:30873022
Translate Bio provides update on lead mRNA therapeutic MRT5005, currently in development for the treatment of cystic fibrosis (CF)
https://globenewswire.com/news-release/2019/02/27/1743808/0/en/Translate-Bio-Provides-Updates-on-Cystic-Fibrosis-CF-and-Ornithine-Transcarbamylase-OTC-Deficiency-Programs.html
MaRS Innovation adds to growing portfolio with two new LAB150 projects to create novel therapeutics for Cystic Fibrosis and Respiratory Syncytial Virus
https://globenewswire.com/news-release/2019/02/27/1743264/0/en/MaRS-Innovation-adds-to-growing-portfolio-with-two-new-LAB150-projects-to-create-novel-therapeutics-for-Cystic-Fibrosis-and-Respiratory-Syncytial-Virus.html
Enhancing the Expression of CFTR Using Antisense Molecules Against MicroRNA miR-145-5p
https://www.atsjournals.org/doi/10.1164/rccm.201901-0019LE
https://www.ncbi.nlm.nih.gov/pubmed/30811944?dopt=Abstract
Transcriptome Profiling and Molecular Therapeutic Advances in Cystic Fibrosis: Recent Insights
https://www.mdpi.com/2073-4425/10/3/180 [Read more…] about Transcriptome Profiling and Molecular Therapeutic Advances in Cystic Fibrosis: Recent Insights
Eloxx Pharmaceuticals evaluating investigational compound ELX-02 for treatment of Cystic Fibrosis in patients with nonsense mutations
https://globenewswire.com/news-release/2019/02/26/1742890/0/en/Eloxx-Pharmaceuticals-Announces-Participation-in-the-HIT-CF-Project-on-Cystic-Fibrosis.html
Eloxx Pharmaceuticals Announces Participation in the HIT-CF Project on Cystic Fibrosis
Eloxx is evaluating ELX-02, its lead investigational compound, for the treatment of Cystic Fibrosis in patients with nonsense mutations [Read more…] about Eloxx Pharmaceuticals evaluating investigational compound ELX-02 for treatment of Cystic Fibrosis in patients with nonsense mutations
Tetrafunctional Block Copolymers Promote Lung Gene Transfer in Newborn Piglets
https://www.ncbi.nlm.nih.gov/pubmed/30897407?dopt=Abstract
Tetrafunctional Block Copolymers Promote Lung Gene Transfer in Newborn Piglets.
Mol Ther Nucleic Acids. 2019 Feb 26;16:186-193
Authors: Caballero I, Riou M, Hacquin O, Chevaleyre C, Barc C, Pezant J, Pinard A, Fassy J, Rezzonico R, Mari B, Heuzé-Vourc’h N, Pitard B, Vassaux G
Abstract
Tetrafunctional block copolymers are molecules capable of complexing DNA. Although ineffective in vitro, studies in mice have shown that the tetrafunctional block copolymer 704 is a more efficient lung gene transfer agent than the cationic liposome GL67A, previously used in a phase II clinical trial in cystic fibrosis patients. In the present study, we compared the gene transfer capacity of the 704-DNA formulation and a cationic liposome-DNA formulation equivalent to GL67A in a larger-animal model, the newborn piglet. Our results indicate an efficacy of the 704-DNA formulation well above one order of magnitude higher than that of the cationic liposome-DNA formulation, with no elevated levels of interleukin-6 (IL-6), taken as a marker of inflammation. Transgene expression was heterogeneous within lung lobes, with expression levels that were below the detection threshold in some samples, while high in other samples. This heterogeneity is likely to be due to the bolus injection procedure as well as to the small volume of injection. The present study highlights the potential of tetrafunctional block copolymers as non-viral vectors for lung gene therapy.
PMID: 30897407 [PubMed – as supplied by publisher]
PubMed:30897407
Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008007
https://www.ncbi.nlm.nih.gov/pubmed/30807572?dopt=Abstract
SAD and MAD of Inhaled AR-501 in Health Adults and P. Aeruginosa Infected Cystic Fibrosis Subjects
https://clinicaltrials.gov/ct2/show/NCT03669614?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=02%2F12%2F2019&lupd_d=14
Condition : Cystic Fibrosis
Interventions : Drug: inhaled AR-501; Drug: inhaled AR-501 placebo
Sponsor : Aridis Pharmaceuticals, Inc.
Recruiting
SAD and MAD of Inhaled AR-501 in Health Adults and P. Aeruginosa Infected Cystic Fibrosis Subjects
NCT03669614
Thu, 13 Sep 2018 12:00:00 EDT
Last Update Posted: 02/26/19 10:27AM
A novel membrane-disruptive antimicrobial peptide from frog skin secretion against cystic fibrosis isolates and evaluation of anti-MRSA effect using Galleria mellonella model
Japonicin-2LF could be potential drug candidate to control MRSA infection in cystic fibrosis patients…
https://www.sciencedirect.com/science/article/pii/S0304416519300479?via%3Dihub
https://www.ncbi.nlm.nih.gov/pubmed/30802593?dopt=Abstract
Correct antibiotic dosing could preserve lung microbial diversity in cystic fibrosis
https://www.sciencedaily.com/releases/2019/02/190222084242.htm [Read more…] about Correct antibiotic dosing could preserve lung microbial diversity in cystic fibrosis
Changes in microbiome diversity following beta-lactam antibiotic treatment are associated with therapeutic versus subtherapeutic antibiotic exposure in cystic fibrosis
Therapeutic and subtherapeutic beta-lactam use is associated with different patterns of changes in CF airway microbial diversity following antibiotic administration.
Changes in microbiome diversity following beta-lactam antibiotic treatment are associated with therapeutic versus subtherapeutic antibiotic exposure in cystic fibrosis.
Cystic fibrosis: We see fungus among us, but should we care?
https://www.ncbi.nlm.nih.gov/pubmed/30797724?dopt=Abstract
Cystic fibrosis: We see fungus among us, but should we care?
J Cyst Fibros. 2019 Feb 20;:
Authors: Hong G, Lechtzin N
PMID: 30797724 [PubMed – as supplied by publisher]
PubMed:30797724
Novel gene therapy approach creates new route to tackle rare, inherited diseases including cystic fibrosis
https://www.eurekalert.org/pub_releases/2019-02/uoih-ngt021719.php
Cystic fibrosis and portal hypertension: Distal splenorenal shunt can prevent the need for future liver transplant
https://www.jpedsurg.org/article/S0022-3468(19)30072-7/fulltext
https://www.ncbi.nlm.nih.gov/pubmed/30792095?dopt=Abstract
A Study Evaluating the Long Term Safety and Efficacy of VX-659 Combination Therapy
https://clinicaltrials.gov/ct2/show/NCT03447262?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=02%2F04%2F2019&lupd_d=14
Condition : Cystic Fibrosis
Interventions : Drug: VX-659; Drug: TEZ; Drug: IVA
Sponsor : Vertex Pharmaceuticals Incorporated
Enrolling by invitation
A Study Evaluating the Long Term Safety and Efficacy of VX-659 Combination Therapy
NCT03447262
Tue, 27 Feb 2018 12:00:00 EST
Last Update Posted: 02/18/19 10:26AM
A Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy
https://clinicaltrials.gov/ct2/show/NCT03525574?recrs=abdf&type=Intr&cond=Cystic+Fibrosis&lupd_s=02%2F04%2F2019&lupd_d=14
Condition : Cystic Fibrosis
Interventions : Drug: VX-445; Drug: TEZ; Drug: IVA
Sponsor : Vertex Pharmaceuticals Incorporated
Enrolling by invitation
A Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy
NCT03525574
Tue, 15 May 2018 12:00:00 EDT
Last Update Posted: 02/18/19 10:26AM
Drug row ‘having enormous impact’ on cystic fibrosis patients
https://news.sky.com/story/drug-row-having-enormous-impact-on-cystic-fibrosis-patients-11639872
Efficient Gene Editing at Major CFTR Mutation Loci
https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(19)30036-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2162253119300368%3Fshowall%3Dtrue
https://www.ncbi.nlm.nih.gov/pubmed/30852378?dopt=Abstract
Efficient Gene Editing at Major CFTR Mutation Loci.
Mol Ther Nucleic Acids. 2019 Feb 16;16:73-81
Authors: Ruan J, Hirai H, Yang D, Ma L, Hou X, Jiang H, Wei H, Rajagopalan C, Mou H, Wang G, Zhang J, Li K, Chen YE, Sun F, Xu J
Abstract
Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Nuclease-mediated precise gene editing (PGE) represents a promising therapy for CF, for which an efficient strategy that is free of viral vector, drug selection, and reporter enrichment (VDR free) is desirable. Here we compared different transfection methods (lipofectamine versus electroporation) and formats (plasmid DNA versus ribonucleoprotein) in delivering the CRISPR/Cas9 elements along with single-stranded oligodeoxynucleotides (ssODNs) to clinically relevant cells targeting major CFTR mutation loci. We demonstrate that, among different combinations, electroporation of CRISPR/Cas9 and guide RNA (gRNA) ribonucleoprotein (Cas9 RNP) is the most effective one. By using this VDR-free method, 4.8% to 27.2% efficiencies were achieved in creating dF508, G542X, and G551D mutations in a wild-type induced pluripotent stem cell (iPSC) line. When it is applied to a patient-derived iPSC line carrying the dF508 mutation, a greater than 20% precise correction rate was achieved. As expected, genetic correction leads to the restoration of CFTR function in iPSC-derived proximal lung organoids, as well as in a patient-derived adenocarcinoma cell line CFPAC-1. The present work demonstrates the feasibility of gene editing-based therapeutics toward monogenic diseases such as CF.
PMID: 30852378 [PubMed – as supplied by publisher]
PubMed:30852378
OPTION: A Trial to Assess the Safety & Efficacy of MS1819 in Patients With Exocrine Pancreatic Insufficiency Due to Cystic Fibrosis (OPTION)
https://clinicaltrials.gov/ct2/show/NCT03746483
Personalization of therapies in rare diseases: a translational approach for the treatment of cystic fibrosis
https://www.ncbi.nlm.nih.gov/pubmed/30761822
https://www.minervamedica.it/en/journals/minerva-pediatrica/article.php?cod=R15Y9999N00A19021307
Personalization of therapies in rare diseases: a translational approach for the treatment of cystic fibrosis.
Mutation-specific therapies and drug repositioning in cystic fibrosis
https://www.minervamedica.it/en/journals/minerva-pediatrica/article.php?cod=R15Y9999N00A19021305
https://www.ncbi.nlm.nih.gov/pubmed/30761820
Mutation-specific therapies and drug repositioning in cystic fibrosis.
Safety and Tolerability Study of Allogeneic Mesenchymal Stem Cell Infusion in Adults With Cystic Fibrosis (CEASE-CF)
https://clinicaltrials.gov/ct2/show/NCT02866721
Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis
https://www.ncbi.nlm.nih.gov/pubmed/30759382
https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30097-X?sf207795786=1
Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis.
Challenges Facing Airway Epithelial Cell-Based Therapy for Cystic Fibrosis
https://www.frontiersin.org/articles/10.3389/fphar.2019.00074/full
https://www.ncbi.nlm.nih.gov/pubmed/30800069?dopt=Abstract
Related Articles [Read more…] about Challenges Facing Airway Epithelial Cell-Based Therapy for Cystic Fibrosis
Study of LAU-7b in the Treatment of Cystic Fibrosis in Adults (APPLAUD)
https://clinicaltrials.gov/ct2/show/NCT03265288
U of S research could advance treatment for Cystic Fibrosis
https://saskatoon.ctvnews.ca/u-of-s-research-could-advance-treatment-for-cystic-fibrosis-1.4287480
HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddz026/5308640
https://www.ncbi.nlm.nih.gov/pubmed/30753450
HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants.
These data suggest that HDACi can serve to level the cellular playing field for correcting CF-causing mutations, a leveling effect that might also extend to other protein misfolding diseases.
Trial to Evaluate Efficacy and Safety of Lenabasum in Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT03451045
UC Berkeley professor collaborates on study to improve cystic fibrosis treatment
‘We’re still waiting’: As cystic fibrosis drugs deliver new hope, not everyone is being swept up by scientific progress
Advances In Cystic Fibrosis Treatment Give Many Hope, But Others Have ‘Panic’ Of Being Left Behind
Adapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease
https://www.frontiersin.org/articles/10.3389/fphar.2019.00020/full
https://www.ncbi.nlm.nih.gov/pubmed/30774592?dopt=Abstract
Adapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease.
Front Pharmacol. 2019;10:20
Authors: Bodas M, Vij N
Abstract
Cystic fibrosis (CF), a fatal genetic disorder predominant in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (Cftr) gene. The most common mutation is the deletion of phenylalanine from the position-508 (F508del-CFTR), resulting in a misfolded-CFTR protein, which is unable to fold, traffic and retain its plasma membrane (PM) localization. The resulting CFTR dysfunction, dysregulates variety of key cellular mechanisms such as chloride ion transport, airway surface liquid (ASL) homeostasis, mucociliary-clearance, inflammatory-oxidative signaling, and proteostasis that includes ubiquitin-proteasome system (UPS) and autophagy. A collective dysregulation of these key homoeostatic mechanisms contributes to the development of chronic obstructive cystic fibrosis lung disease, instead of the classical belief focused exclusively on ion-transport defect. Hence, therapeutic intervention(s) aimed at rescuing chronic CF lung disease needs to correct underlying defect that mediates homeostatic dysfunctions and not just chloride ion transport. Since targeting all the myriad defects individually could be quite challenging, it will be prudent to identify a process which controls almost all disease-promoting processes in the CF airways including underlying CFTR dysfunction. There is emerging experimental and clinical evidence that supports the notion that impaired cellular proteostasis and autophagy plays a central role in regulating pathogenesis of chronic CF lung disease. Thus, correcting the underlying proteostasis and autophagy defect in controlling CF pulmonary disease, primarily via correcting the protein processing defect of F508del-CFTR protein has emerged as a novel intervention strategy. Hence, we discuss here both the rationale and significant therapeutic utility of emerging proteostasis and autophagy modulating drugs/compounds in controlling chronic CF lung disease, where targeted delivery is a critical factor-influencing efficacy.
PMID: 30774592 [PubMed]
PubMed:30774592
Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease
https://www.mdpi.com/1424-8247/12/1/23
https://www.ncbi.nlm.nih.gov/pubmed/30717260
Nanomedicine for Cystic Fibrosis
https://journals.sagepub.com/doi/abs/10.1177/2472630318824334?journalCode=jlad
Discovery could improve cystic fibrosis treatment
https://medicalxpress.com/news/2019-01-discovery-cystic-fibrosis-treatment.html
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/study/NCT03251092
A Phase 2b Randomised, Placebo Controlled Study of OligoG in Patients With Cystic Fibrosis (CFmised, Double-blind, Parallel-group Study of Alginate Oligosaccharide)
https://clinicaltrials.gov/ct2/show/NCT03822455
A Phase 2b Randomised, Placebo Controlled Study of OligoG in Patients With Cystic Fibrosis (CFmised, Double-blind, Parallel-group Study of Alginate Oligosaccharide)
Go to sections
Brief Summary:
A double-blind, randomised study of OligoG DPI compared to placebo DPI, both on top of standard-of-care, to assess safety, efficacy and tolerability. Adult patients with Cystic Fibrosis will be included in the study.
Condition or disease Intervention/treatment Phase
Cystic Fibrosis
Drug: OligoG DPI
Phase 2
Phase 3
Detailed Description:
The alginate oligosaccharide OligoG CF-5/20 dry powder for inhalation (OligoG DPI) represents a novel therapeutic approach for patients with cystic fibrosis (CF). OligoG has been shown to release stagnant mucus, modulate sputum rheology and disrupt the biofilm formation often typically observed in CF. These properties will in turn facilitate mucus clearance and promote effectiveness of antibiotic therapy against the chronic pulmonary infections characteristic of CF.
Patients with CF (age 18 years or older) will be eligible to participate in this study.
The design will be a randomised, blinded, placebo-controlled pilot study for proof of concept that OligoG DPI can improve lung function in adult CF patients. Study medication will be given twice daily for twelve weeks on top of standard of care (SOC). Thirty-three patients will be included, out of which twenty-two shall receive OligoG, and eleven shall receive placebo.
Following a 4 week wash out period, patients will be given open-label OligoG twice daily, in addition to standard of care, for 12 months.
The primary endpoint will be absolute change i percent predicted FEV1
Exploratory parameters will include sputum microbiology.
Study Design
Go to sections
Study Type : Interventional
Estimated Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomised, double blind, placebo controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Patients will be randomised to receive OligoG or placebo DPI. The investigational medicinal products will have identical appearance
Primary Purpose: Treatment
Official Title: A Phase 2b Randomised, Double-blind, Parallel-group Study of Alginate Oligosaccharide (OligoG) Dry Powder Inhalation in Addition to Standard of Care Compared to Placebo in Addition to Standard of Care in Patients With Cystic Fibrosis (CF)
Estimated Study Start Date : April 3, 2019
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : October 30, 2019
Safety, Tolerability, and Pharmacokinetics of PTI-808, PTI-801, and PTI-428 Combination Therapy in Subjects With Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT03500263
TMEM16A in Cystic Fibrosis: Activating or Inhibiting?
https://www.frontiersin.org/articles/10.3389/fphar.2019.00003/full
https://www.ncbi.nlm.nih.gov/pubmed/30761000
TMEM16A in Cystic Fibrosis: Activating or Inhibiting?
Novel Therapeutic Approaches for Treatment of CF Patients With W1282X Premature Termination Codon Mutations
https://clinicaltrials.gov/ct2/show/NCT03624101
‘A hopeful time in CF’; Research leads to new understanding in cystic fibrosis treatment
https://www.cbc.ca/news/canada/saskatchewan/a-hopeful-time-in-cf-research-leads-to-new-understanding-in-cystic-fibrosis-treatment-1.4994630
Philadelphia gene therapy company awarded $4.5M from Cystic Fibrosis Foundation
https://www.bizjournals.com/philadelphia/news/2019/01/23/talee-bio-cystic-fibrosis-grant-chop-militia-hill.html
Personalized Theratyping Trial
https://clinicaltrials.gov/ct2/show/NCT03587961
Study of VX-121 in Healthy Subjects and in Subjects With Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT03768089
Nanobody-based binding assay for the discovery of potent inhibitors of CFTR inhibitory factor (Cif)
https://www.sciencedirect.com/science/article/pii/S0003267019300273?via%3Dihub
https://www.ncbi.nlm.nih.gov/pubmed/30832908?dopt=Abstract
Related Articles
Nanobody-based binding assay for the discovery of potent inhibitors of CFTR inhibitory factor (Cif).
Anal Chim Acta. 2019 May 30;1057:106-113
Authors: Vasylieva N, Kitamura S, Dong J, Barnych B, Hvorecny KL, Madden DR, Gee SJ, Wolan DW, Morisseau C, Hammock BD
Abstract
Lead identification and optimization are essential steps in the development of a new drug. It requires cost-effective, selective and sensitive chemical tools. Here, we report a novel method using nanobodies that allows the efficient screening for potent ligands. The method is illustrated with the cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), a virulence factor secreted by the opportunistic pathogen Pseudomonas aeruginosa. 18 nanobodies selective to Cif were isolated by bio-panning from nanobody-phage library constructed from immunized llama. 8 out of 18 nanobodies were identified as potent inhibitors of Cif enzymatic activity with IC50s in the range of 0.3-6.4 μM. A nanobody VHH219 showed high affinity (KD = 0.08 nM) to Cif and the highest inhibitory potency, IC50 = 0.3 μM. A displacement sandwich ELISA (dsELISA) with VHH219 was then developed for classification of synthetic small molecule inhibitors according their inhibitory potency. The developed assay allowed identification of new inhibitor with highest potency reported so far (0.16 ± 0.02 μM). The results from dsELISA assay correlates strongly with a conventional fluorogenic assay (R = 0.9998) in predicting the inhibitory potency of the tested compounds. However, the novel dsELISA is an order of magnitude more sensitive and allows the identification and ranking of potent inhibitors missed by the classic fluorogenic assay method. These data were supported with Octet biolayer interferometry measurements. The novel method described herein relies solely on the binding properties of the specific neutralizing nanobody, and thus is applicable to any pharmacological target for which such a nanobody can be found, independent of any requirement for catalytic activity.
PMID: 30832908 [PubMed – in process]
PubMed:30832908
Human MesenchymAl Stem Cells Infusion in Patients With Cystic Fibrosis (HAPI)
https://clinicaltrials.gov/ct2/show/NCT03058068
Vast Therapeutics Announces Funding from Cystic Fibrosis Foundation for Further Development of BIOC51
https://www.prnewswire.com/news-releases/vast-therapeutics-announces-funding-from-cystic-fibrosis-foundation-for-further-development-of-bioc51-300765000.html
A DDI Study of FDL169 and FDL176 in Healthy Subjects
https://clinicaltrials.gov/ct2/show/NCT03756922
Sponsor:
Flatley Discovery Lab LLC
Information provided by (Responsible Party):
Flatley Discovery Lab LLC
Brief Summary:
A DDI study to assess the safety, tolerability and pharmacokinetics of both; doses of FDL176 with and without co-administration of FDL169 and doses of FDL169 with and without co-administration of FDL176.
Condition or disease Intervention/treatment Phase
Cystic Fibrosis
Drug: FDL169
Drug: FDL176
Phase 1
Detailed Description:
This is an open-label, non-randomised study. Enrolment will be in two parallel and independent parts. Part 1 will assess the safety, tolerability and pharmacokinetics of single doses of FDL176 with and without co-administration of FDL169. Part 2 will assess the safety, tolerability and pharmacokinetics of repeated doses of FDL169 with and without co-administration of FDL176.
Study Design
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open Label, Drug-Drug Interaction Study of FDL169 and FDL176 in Healthy Subjects
Actual Study Start Date : November 27, 2018
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019
Delivering on the promise of gene editing for cystic fibrosis
https://www.sciencedirect.com/science/article/pii/S2352304218301363?via%3Dihub
https://www.ncbi.nlm.nih.gov/pubmed/31193992?dopt=Abstract
Delivering on the promise of gene editing for cystic fibrosis.
Genes Dis. 2019 Jun;6(2):97-108
Authors: Hodges CA, Conlon RA
Abstract
In this review, we describe a path for translation of gene editing into therapy for cystic fibrosis (CF). Cystic fibrosis results from mutations in the CFTR gene, with one allele predominant in patient populations. This simple, genetic etiology makes gene editing appealing for treatment of this disease. There already have been success in applying this approach to cystic fibrosis in cell and animal models, although these advances have been modest in comparison to advances for other disease. Less than six years after its first demonstration in animals, CRISPR/Cas gene editing is in early clinical trials for several disorders. Most clinical trials, thus far, attempt to edit genes in cells of the blood lineages. The advantage of the blood is that the stem cells are known, can be isolated, edited, selected, expanded, and returned to the body. The likely next trials will be in the liver, which is accessible to many delivery methods. For cystic fibrosis, the biggest hurdle is to deliver editors to other, less accessible organs. We outline a path by which delivery can be improved. The translation of new therapies doesn’t occur in isolation, and the development of gene editors is occurring as advances in gene therapy and small molecule therapeutics are being made. The advances made in gene therapy may help develop delivery vehicles for gene editing, although major improvements are needed. Conversely, the approval of effective small molecule therapies for many patients with cystic fibrosis will raise the bar for translation of gene editing.
PMID: 31193992 [PubMed]
PubMed:31193992
The lung and gut microbiome: what has to be taken into consideration for cystic fibrosis?
https://www.cysticfibrosisjournal.com/article/S1569-1993(18)30931-7/fulltext
The lung and gut microbiome: what has to be taken into consideration for cystic fibrosis?
Clinical Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of POL6014 in Patients With CF
https://clinicaltrials.gov/ct2/show/NCT03748199
After a cystic fibrosis ‘miracle,’ researchers are exploring ways to reach millions more
https://www.uab.edu/news/research/item/10360-after-a-cystic-fibrosis-miracle-researchers-are-exploring-ways-to-reach-millions-more
HealthDay speculates that experimental cystic fibrosis drug combo could be ‘breakthrough’ and ‘game-changing’
Safety, Pharmacokinetics and Pharmacodynamics Study of Inhaled QBW276 in Patients With Cystic Fibrosis
https://clinicaltrials.gov/ct2/show/NCT02566044
Study to Evaluate the Safety & Tolerability of MRT5005 Administered by Nebulization in Adults With Cystic Fibrosis (RESTORE-CF)
https://clinicaltrials.gov/ct2/show/NCT03375047
Stem Cell Transplant Research Leads to Cystic Fibrosis Breakthrough
https://www.raredr.com/news/stem-cell-transplant-research-leads-to-cystic-fibrosis-breakthrough
Stem Cell Research for Cystic Fibrosis Leaps Forward
https://www.adelaide.edu.au/news/news101662.html
Newly Discovered Cell Type May Fuel Cystic Fibrosis … surprising insight could provide foundation for future cure
https://www.scientificamerican.com/article/newly-discovered-cell-type-may-fuel-cystic-fibrosis/
Cystic fibrosis clues found in newly identified cell type
Biomarkers: Their Role in CFTR Modulator Therapies from Early Development to the Clinic
https://www.atsjournals.org/doi/10.1164/rccm.201801-0177ED
https://www.ncbi.nlm.nih.gov/pubmed/29406823?dopt=Abstract
Related Articles
Biomarkers: Their Role in CFTR Modulator Therapies from Early Development to the Clinic.
Am J Respir Crit Care Med. 2018 06 01;197(11):1375-1376
Authors: Bell SC, Wood ME
PMID: 29406823 [PubMed – indexed for MEDLINE]
PubMed:29406823
Cystic Fibrosis – Reddit
https://www.reddit.com/r/CysticFibrosis/