Cystic Fibrosis Treatment Report

www.CysticFibrosisTreatmentReport.com

CFTR modulators

CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes

https://www.frontiersin.org/articles/10.3389/fcimb.2020.00372/full

https://www.ncbi.nlm.nih.gov/pubmed/32793514?dopt=Abstract

Related Articles

CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes.

Front Cell Infect Microbiol. 2020;10:372

Authors: Currie AJ, Main ET, Wilson HM, Armstrong-James D, Warris A

Abstract

Excessive inflammation by phagocytes during Aspergillus fumigatus infection is thought to promote lung function decline in CF patients. CFTR modulators have been shown to reduce A. fumigatus colonization in vivo, however, their antifungal and anti-inflammatory mechanisms are unclear. Other treatments including azithromycin and acebilustat may dampen Aspergillus-induced inflammation due to their immunomodulatory properties. Therefore, we set out in this study to determine the effects of current CF therapies on ROS production and fungal killing, either direct or indirect by enhancing antifungal immune mechanisms in peripheral blood immune cells from CF patients upon A. fumigatus infection. Isolated peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from CF patients and healthy volunteers were challenged with A. fumigatus following pre-treatment with CFTR modulators, azithromycin or acebilustat. Ivacaftor/lumacaftor treated CF and control subject PMNs resulted in a significant reduction (p < 0.05) in Aspergillus-induced ROS. For CF PBMC, Aspergillus-induced ROS was significantly reduced when pre-treated with ivacaftor alone (p < 0.01) or in combination with lumacaftor (p < 0.01), with a comparable significant reduction in control subject PBMC (p < 0.05). Azithromycin and acebilustat had no effect on ROS production by CF or control subject phagocytes. None of the treatments showed an indirect or direct antifungal activity. In summary, CFTR modulators have potential for additional immunomodulatory benefits to prevent or treat Aspergillus-induced inflammation in CF. The comparable effects of CFTR modulators observed in phagocytes from control subjects questions their exact mechanism of action. PMID: 32793514 [PubMed - in process] PubMed:32793514

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

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

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

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

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

Back to top