scholarly journals Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2793
Author(s):  
Isabelle Fajac ◽  
Isabelle Sermet
Keyword(s):  
Cystic Fibrosis ◽  
Protein Function ◽  
Protein A ◽  
Autosomal Recessive Disorder ◽  
New Drugs ◽  
Gene Encoding ◽  
Disease Modifying Drugs ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Cftr Modulators

Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function, and they will benefit many patients with cystic fibrosis in the near future. However, some patients bear rare mutations that are not yet eligible for CFTR modulators, although they might be amenable to these new disease-modifying drugs. Moreover, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon. The purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations ineligible for CFTR modulators. One approach is to broaden the numbers of mutations eligible for CFTR modulators. This requires developing strategies to evaluate drugs in populations bearing very rare genotypes. Other approaches aiming at correcting the CFTR defect develop new mutation-specific or mutation-agnostic therapies for mutations that do not produce a CFTR protein: readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA- or DNA-based, and cell-based therapies. Most of these approaches are in pre-clinical development or, for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.

scholarly journals Cytoskeleton regulators CAPZA2 and INF2 associate with CFTR to control its plasma membrane levels under EPAC1 activation

2020 ◽  
Vol 477 (13) ◽  
pp. 2561-2580
Author(s):  
João D. Santos ◽  
Francisco R. Pinto ◽  
João F. Ferreira ◽  
Margarida D. Amaral ◽  
Manuela Zaccolo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Protein A ◽  
Bioinformatic Analysis ◽  
Apical Surface ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Gene Encoding ◽  
Cftr Protein ◽  
Related Proteins ◽  
Cystic Fibrosis Transmembrane

Cystic Fibrosis (CF), the most common lethal autosomic recessive disorder among Caucasians, is caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, a cAMP-regulated chloride channel expressed at the apical surface of epithelial cells. Cyclic AMP regulates both CFTR channel gating through a protein kinase A (PKA)-dependent process and plasma membane (PM) stability through activation of the exchange protein directly activated by cAMP1 (EPAC1). This cAMP effector, when activated promotes the NHERF1:CFTR interaction leading to an increase in CFTR at the PM by decreasing its endocytosis. Here, we used protein interaction profiling and bioinformatic analysis to identify proteins that interact with CFTR under EPAC1 activation as possible regulators of this CFTR PM anchoring. We identified an enrichment in cytoskeleton related proteins among which we characterized CAPZA2 and INF2 as regulators of CFTR trafficking to the PM. We found that CAPZA2 promotes wt-CFTR trafficking under EPAC1 activation at the PM whereas reduction of INF2 levels leads to a similar trafficking promotion effect. These results suggest that CAPZA2 is a positive regulator and INF2 a negative one for the increase of CFTR at the PM after an increase of cAMP and concomitant EPAC1 activation. Identifying the specific interactions involving CFTR and elicited by EPAC1 activation provides novel insights into late CFTR trafficking, insertion and/or stabilization at the PM and highlighs new potential therapeutic targets to tackle CF disease.

scholarly journals Progress Toward The Synthesis Of Labeled Derivatives Of The Cystic Fibrosis Drug Ivacaftor

2021 ◽  
Author(s):  
Salma Elmallah
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Genetic Diseases ◽  
Early Death ◽  
Open Probability ◽  
Gene Encoding ◽  
Short Period ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Orally Bioavailable

Cystic fibrosis (CF) is one of the most common genetic diseases, affecting approximately 70,000 people worldwide causing severe complications and often leading to early death. CF is caused by a mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein which is responsible for fluid and ion transport through epithelial membranes maintaining the formation of a thin slippery mucous layer. CFTR mutations either lead to a trafficking defect where the CFTR protein does not reach the plasma membrane or a gating defect where CFTR protein at the plasma membrane does not function properly. Treatment of cystic fibrosis usually addresses the symptoms to overcome the complications of the disease such as pneumonia, lung infections, pancreatitis, maldigestion and infertility. Vertex pharmaceuticals has been interested in developing small molecules that have the ability to interact with mutated CFTR proteins, aiding in their delivery to the cell membrane and/or restoring their channel function. VX-770 is an orally bioavailable potentiator that has the ability to improve the gating activity and increasing the open probability of CFTR protein in patients carrying the G551D mutation. VX770, Ivacaftor, was recently approved by the US FDA after showing very good improvements in the lung function in CF patients with good safety profile. Our research is focusing on the synthesis of VX770 under mild conditions and formation of labeled derivatives to help in the understanding of its exact mode of action. Different methods were developed toward the synthesis of the two main components, LHS and RHS, of VX770 by using less harsh conditions for a short period of time. We were successfully able to make two photoaffinity labeled derivatives, aryl azide and benzophenone derivatives, which will be beneficial in tracking the drug molecule and revealing the exact site of interaction between the drug and the protein. Synthesis of VX770 fragments was is another focus of interest in our research as they will provide us with information about the best positions for further derivatization.

scholarly journals Progress Toward The Synthesis Of Labeled Derivatives Of The Cystic Fibrosis Drug Ivacaftor

2021 ◽  
Author(s):  
Salma Elmallah
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Genetic Diseases ◽  
Early Death ◽  
Open Probability ◽  
Gene Encoding ◽  
Short Period ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Orally Bioavailable

Cystic fibrosis (CF) is one of the most common genetic diseases, affecting approximately 70,000 people worldwide causing severe complications and often leading to early death. CF is caused by a mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein which is responsible for fluid and ion transport through epithelial membranes maintaining the formation of a thin slippery mucous layer. CFTR mutations either lead to a trafficking defect where the CFTR protein does not reach the plasma membrane or a gating defect where CFTR protein at the plasma membrane does not function properly. Treatment of cystic fibrosis usually addresses the symptoms to overcome the complications of the disease such as pneumonia, lung infections, pancreatitis, maldigestion and infertility. Vertex pharmaceuticals has been interested in developing small molecules that have the ability to interact with mutated CFTR proteins, aiding in their delivery to the cell membrane and/or restoring their channel function. VX-770 is an orally bioavailable potentiator that has the ability to improve the gating activity and increasing the open probability of CFTR protein in patients carrying the G551D mutation. VX770, Ivacaftor, was recently approved by the US FDA after showing very good improvements in the lung function in CF patients with good safety profile. Our research is focusing on the synthesis of VX770 under mild conditions and formation of labeled derivatives to help in the understanding of its exact mode of action. Different methods were developed toward the synthesis of the two main components, LHS and RHS, of VX770 by using less harsh conditions for a short period of time. We were successfully able to make two photoaffinity labeled derivatives, aryl azide and benzophenone derivatives, which will be beneficial in tracking the drug molecule and revealing the exact site of interaction between the drug and the protein. Synthesis of VX770 fragments was is another focus of interest in our research as they will provide us with information about the best positions for further derivatization.

scholarly journals Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations

2018 ◽  
Vol 314 (4) ◽  
pp. L529-L543 ◽  
Author(s):  
Misak Harutyunyan ◽  
Yunjie Huang ◽  
Kyu-Shik Mun ◽  
Fanmuyi Yang ◽  
Kavisha Arora ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Personalized Medicine ◽  
Therapeutic Option ◽  
Protein A ◽  
Common Life ◽  
Large Numbers ◽  
Wide Range ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting ~1 in 3,500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, more than 2,000 CFTR mutations have been identified, which produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality. Research has focused on identifying small molecules, or modulators, that can restore CFTR function. In recent years, two modulators, ivacaftor (Kalydeco) and lumacaftor/ivacaftor (Orkambi), have been approved by the U.S. Food and Drug Administration to treat CF patients with certain CFTR mutations. The development of these modulators has served as proof-of-concept that targeting CFTR by modulators is a viable therapeutic option. Efforts to discover new modulators that could deliver a wider and greater clinical benefit are still ongoing. However, traditional randomized controlled trials (RCTs) require large numbers of patients and become impracticable to test the modulators’ efficacy in CF patients with CFTR mutations at frequencies much lower than 1%, suggesting the need for personalized medicine in these CF patients.

scholarly journals Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Breathe ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 210112
Author(s):  
Daniel H. Tewkesbury ◽  
Rebecca C. Robey ◽  
Peter J. Barry
Keyword(s):  
Cystic Fibrosis ◽  
Precision Medicine ◽  
Real World ◽  
Chloride Ion ◽  
Transmembrane Conductance Regulator ◽  
Therapeutic Approaches ◽  
Transmembrane Conductance ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

scholarly journals The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy

2019 ◽  
Vol 13 ◽  
pp. 175346661984442 ◽  
Author(s):  
Sherstin T. Lommatzsch ◽  
Jennifer L. Taylor-Cousar
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Evidence ◽  
Anion Channel ◽  
The United States ◽  
New Era ◽  
Sweat Chloride ◽  
Cftr Protein ◽  
Surface Liquid ◽  
Cftr Modulators ◽  
Epithelial Sodium Channel Enac

Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity. Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition. Traditionally, CF has been symptomatically managed, but over the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor. To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources.

scholarly journals Elexacaftor/tezacaftor/ivacaftor in an individual with cystic fibrosis caused by a N1303K CFTR variant and infected with Mycobacterium abscessus

2021 ◽  
Author(s):  
E. Elson ◽  
Paula Capel ◽  
Jessica Haynes ◽  
Stephanie Duehlmeyer ◽  
Michelle Fischer ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Mycobacterium Abscessus ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane ◽  
Protein Variants ◽  
Cftr Modulators ◽  
Clinical Stability

This report describes a case of a 15-year-old male with cystic fibrosis caused by N1303K and Q493X cystic fibrosis transmembrane conductance regulator (CFTR) protein variants. In this case, CFTR modulators including tezacaftor/ivacaftor and subsequently elexacaftor/tezacaftor/ivacaftor were utilized and resulted in clinical stability and improvement.

scholarly journals Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 123
Author(s):  
Aravind Thavamani ◽  
Iman Salem ◽  
Thomas J. Sferra ◽  
Senthilkumar Sankararaman
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Disorder ◽  
Vital Role ◽  
Immune Functions ◽  
Gene Encoding ◽  
Gut Dysbiosis ◽  
Multiple Organs ◽  
Fluid Regulation ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is the most common lethal, multisystemic genetic disorder in Caucasians. Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein are responsible for impairment of epithelial anionic transport, leading to impaired fluid regulation and pH imbalance across multiple organs. Gastrointestinal (GI) manifestations in CF may begin in utero and continue throughout the life, resulting in a chronic state of an altered intestinal milieu. Inherent dysfunction of CFTR leads to dysbiosis of the gut. This state of dysbiosis is further perpetuated by acquired factors such as use of antibiotics for recurrent pulmonary exacerbations. Since the gastrointestinal microbiome and their metabolites play a vital role in nutrition, metabolic, inflammatory, and immune functions, the gut dysbiosis will in turn impact various manifestations of CF—both GI and extra-GI. This review focuses on the consequences of gut dysbiosis and its metabolic implications on CF disease and possible ways to restore homeostasis.

scholarly journals Potentiators exert distinct effects on human, murine, and Xenopus CFTR

2016 ◽  
Vol 311 (2) ◽  
pp. L192-L207 ◽  
Author(s):  
Guiying Cui ◽  
Netaly Khazanov ◽  
Brandon B. Stauffer ◽  
Daniel T. Infield ◽  
Barry R. Imhoff ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Binding Sites ◽  
Pharmacophore Modeling ◽  
New Drugs ◽  
Molecular Pharmacology ◽  
Specific Behavior ◽  
Lead Compounds ◽  
Cftr Mutations ◽  
Different Origins ◽  
Insight Into

VX-770 (Ivacaftor) has been approved for clinical usage in cystic fibrosis patients with several CFTR mutations. Yet the binding site(s) on CFTR for this compound and other small molecule potentiators are unknown. We hypothesize that insight into this question could be gained by comparing the effect of potentiators on CFTR channels from different origins, e.g., human, mouse, and Xenopus (frog). In the present study, we combined this comparative molecular pharmacology approach with that of computer-aided drug discovery to identify and characterize new potentiators of CFTR and to explore possible mechanism of action. Our results demonstrate that 1) VX-770, NPPB, GlyH-101, P1, P2, and P3 all exhibited ortholog-specific behavior in that they potentiated hCFTR, mCFTR, and xCFTR with different efficacies; 2) P1, P2, and P3 potentiated hCFTR in excised macropatches in a manner dependent on the degree of PKA-mediated stimulation; 3) P1 and P2 did not have additive effects, suggesting that these compounds might share binding sites. Also 4) using a pharmacophore modeling approach, we identified three new potentiators (IOWH-032, OSSK-2, and OSSK-3) that have structures similar to GlyH-101 and that also exhibit ortholog-specific potentiation of CFTR. These could potentially serve as lead compounds for development of new drugs for the treatment of cystic fibrosis. The ortholog-specific behavior of these compounds suggest that a comparative pharmacology approach, using cross-ortholog chimeras, may be useful for identification of binding sites on human CFTR.

scholarly journals Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X

2021 ◽  
Author(s):  
Wren E. Michaels ◽  
Cecilia Pena-Rasgado ◽  
Rusudan Kotaria ◽  
Robert J. Bridges ◽  
Michelle L. Hastings
Keyword(s):  
Cystic Fibrosis ◽  
Protein Function ◽  
Antisense Oligonucleotides ◽  
Gene Mutations ◽  
Severe Form ◽  
Open Reading Frame ◽  
Common Mutation ◽  
Reading Frame ◽  
Protein Levels ◽  
Cftr Protein

CFTR gene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of low CFTR mRNA expression as a result of nonsense mediated mRNA decay (NMD), as well as production of a non-functional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations, due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs) designed to induce skipping of exons in order to restore the mRNA open reading frame have shown therapeutic promise pre-clinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, including CFTR p.W1282X, the 5th most common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from homozygote CFTR-W1282X patients. These results support the use of ASOs in treating CF patients with CFTR class I mutations in exon 23 that result in unstable CFTR mRNA and truncations of the CFTR protein.

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