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Journal of Translational Medicine Apr 2017Study of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use. (Review)
Review
OBJECTIVES
Study of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use.
METHODS
Extensive literature search using individual and a combination of key words related to cystic fibrosis therapeutics.
KEY FINDINGS
Cystic fibrosis is an autosomal recessive disorder due to mutations in CFTR gene leading to abnormality of chloride channels in mucus and sweat producing cells. Respiratory system and GIT are primarily involved but eventually multiple organs are affected leading to life threatening complications. Management requires drug therapy, extensive physiotherapy and nutritional support. Previously, the focus was on symptomatic improvement and complication prevention but recently the protein rectifiers are being studied which are claimed to correct underlying structural and functional abnormalities. Some improvement is observed by the corrector drugs. Other promising approaches are gene therapy, targeting of cellular interactomes, and newer drugs for symptomatic improvement.
CONCLUSIONS
The treatment has a long way to go as most of the existing therapeutics is for older children. Other limiting factors include mutation class, genetic profile, drug interactions, adverse effects, and cost. Novel approaches like gene transfer/gene editing, disease modeling and search for alternative targets are warranted.
Topics: Cystic Fibrosis; Drug Discovery; Genetic Predisposition to Disease; Humans; Models, Biological
PubMed: 28449677
DOI: 10.1186/s12967-017-1193-9 -
Annual Review of Medicine Jan 2022Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in , the cystic fibrosis transmembrane conductance regulator gene. People with CF... (Review)
Review
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in , the cystic fibrosis transmembrane conductance regulator gene. People with CF experience a wide variety of medical conditions that affect the pulmonary, endocrine, gastrointestinal, pancreatic, biliary, and reproductive systems. Traditionally, CF carriers, with one defective copy of , were not thought to be at risk for CF-associated diseases. However, an emerging body of literature suggests that heterozygotes are at increased risk for many of the same conditions as homozygotes. For example, heterozygotes appear to be at increased risk for chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis. In the United States alone, there are almost 10 million CF carriers. Universal newborn screening and prenatal genetic screening will identify more. Thus, there is a critical need to develop more precise estimates of health risks attributable to the CF carrier state across the lifespan.
Topics: Cystic Fibrosis; Female; Genetic Testing; Heterozygote; Humans; Infant, Newborn; Mutation; Neonatal Screening; Phenotype; Pregnancy
PubMed: 35084992
DOI: 10.1146/annurev-med-042120-020148 -
Annual Review of Medicine Jan 2023Cystic fibrosis (CF) is an inherited multisystemic disease that can cause progressive bronchiectasis, pancreatic endocrine and exocrine insufficiency, distal intestinal... (Review)
Review
Cystic fibrosis (CF) is an inherited multisystemic disease that can cause progressive bronchiectasis, pancreatic endocrine and exocrine insufficiency, distal intestinal obstruction syndrome, liver dysfunction, and other disorders. Traditional therapies focused on the treatment or prevention of damage to each organ system with incremental modalities such as nebulized medications for the lungs, insulin for diabetes, and supplementation with pancreatic enzymes. However, the advent of highly effective modulator therapies that target specific cystic fibrosis transmembrane conductance regulator protein malformations resulting from individual genetic mutations has transformed the lives and prognosis for persons with CF.
Topics: Humans; Cystic Fibrosis; Prognosis; Mutation; Diabetes Mellitus; Aminophenols
PubMed: 35973718
DOI: 10.1146/annurev-med-042921-021447 -
Boletin Medico Del Hospital Infantil de... 2021Cystic fibrosis is an autosomal recessive genetic disease, mainly in Caucasian children and young adults. It is caused by pathogenic variants in the CFTR (cystic...
Cystic fibrosis is an autosomal recessive genetic disease, mainly in Caucasian children and young adults. It is caused by pathogenic variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which results in increased viscosity and difficult mucus clearance. The main organ affected is the lung, the pancreas, sweat glands, intestine, liver, nasal mucosa, salivary glands, and reproductive tract. The clinical manifestations vary, ranging from the most frequent pulmonary symptoms of obstructive disease to gastrointestinal manifestations relatection of pathogenic variants in the CFTR gene allow the diagnosis to be integrated. Cystic fibrosis management consists of three main strategies: firstly, to keep the airway free of secretion; secondly, to keep the airway free of infection; and finally, to maintain an optimal nutritional status. Therapies that seek to correct alterations in the CFTR gene are focused on avoiding a pathogenic nonsense variant, correcting folding, increasing trafficking to the plasma membrane, or increasing the function of the CFTR channel. Other therapies still under development include gene therapy, genome editing, and antisense oligonucleotides to modify the expression of this gene.
Topics: Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lung; Mutation; Young Adult
PubMed: 34934215
DOI: 10.24875/BMHIM.20000372 -
Archivos Argentinos de Pediatria Feb 2021The present revision of the Guide for the diagnosis and treatment of patients with cystic fibrosis published in 2014 aims to update the knowledge about various aspects...
The present revision of the Guide for the diagnosis and treatment of patients with cystic fibrosis published in 2014 aims to update the knowledge about various aspects related to the clinical management of the disease, according to the scientific advances published and in development in recent years. Only new topics will be discussed here and those that, in light of the research, require modification, so the content of the previous guide remains valid in the rest of the aspects. The updated aspects range over the diagnosis of the disease due to the changes made in the sweat test, the neonatal screening and molecular biology, the update of follow-up studies, such as the Lung Clearance Index and the Nuclear Magnetic Resonance, and modifications regarding the nutritional area (diabetes secondary to cystic fibrosis) and the physiotherapy treatment and pulmonary rehabilitation.
Topics: Cystic Fibrosis; Humans; Infant, Newborn; Neonatal Screening; Physical Therapy Modalities; Respiratory Function Tests
PubMed: 33459002
DOI: 10.5546/aap.2021.s17 -
Seminars in Respiratory and Critical... Dec 2019With the improving survival of cystic fibrosis (CF) patients and the advent of highly effective cystic fibrosis transmembrane conductance regulator therapy, the clinical... (Review)
Review
With the improving survival of cystic fibrosis (CF) patients and the advent of highly effective cystic fibrosis transmembrane conductance regulator therapy, the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is an acute pulmonary exacerbation. Clinical and microbial epidemiology studies of CF pulmonary exacerbations continue to provide important insight into the disease course, prognosis, and complications. This work has now led to a number of large scale clinical trials with the goal of improving the treatment paradigm for CF pulmonary exacerbation. The primary goal of this review is to provide a summary of the pathophysiology, the clinical epidemiology, microbial epidemiology, outcome and the treatment of CF pulmonary exacerbation.
Topics: Adult; Anti-Bacterial Agents; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Forced Expiratory Volume; Humans; Lung; Molecular Targeted Therapy; Randomized Controlled Trials as Topic
PubMed: 31659730
DOI: 10.1055/s-0039-1697975 -
Srpski Arhiv Za Celokupno Lekarstvo 2012Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of CFTR protein, i.e. chloride channel present in the apical... (Review)
Review
Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of CFTR protein, i.e. chloride channel present in the apical membrane of respiratory, digestive, reproductive and sweat glands epithelium. It primarily occurs in the Caucasians, while being considerably or excep tionally rare in persons of other races. Absence, deficit or structural and functional abnormalities of CFTR protein lead to mucosal hyperconcentration in the respiratory, digestive and reproductive systems and malabsorption of chloride and sodium in the sweat glands. Thus, the clinical features of patients' with CF are predominated by respiratory, digestive and reproductive disorders, as well as the tendency to dehydration in the condition of increased sweating. Beside genotype variations, the degree of disease manifestation is also essentially influenced by various exogenous factors, such as the frequency and severity of respiratory infections, the level of aero-pollution, quality of immunoprophylaxis, patients' nutritional condition and other. Chloride concentration of over 60 mmol/L in sweat, a high level of immunoreactive chymotrypsinogen in blood and the verification of homozygous mutation of CFTR gene are the basic methods in the diagnostics of the disease. CF belongs to the group of severe and complex chronic diseases, and therefore requires multidisciplinary therapeutic approach. Owing to the improvement of healthcare provision, most patients with CF now survive into adulthood. In addition, their quality of life is also considerably improved.
Topics: Cystic Fibrosis; Humans
PubMed: 22650116
DOI: No ID Found -
Journal of Cystic Fibrosis : Official... Oct 2019Cystic Fibrosis Related Diabetes Mellitus (CFRD) drives excess pulmonary morbidity and mortality in patients with cystic fibrosis (CF). The recommended treatment is... (Review)
Review
Cystic Fibrosis Related Diabetes Mellitus (CFRD) drives excess pulmonary morbidity and mortality in patients with cystic fibrosis (CF). The recommended treatment is insulin therapy. Insulin therapy in CF should be customized to the specific patient. CF patients typically require intensive insulin regimens such as multiple daily injections or insulin pump therapy, but frequently require lower doses than in type 1 diabetes mellitus. Patients with CF may also need insulin to cover intravenous or enteral feedings. Pre-diabetic glycaemic abnormalities are also associated with clinical decline in cystic fibrosis prior to the diagnosis of CFRD, however, whether and how this should be treated is not fully determined. There is also interest, but inadequate data regarding other treatments besides insulin (i.e., oral medications) for treatment of pre-diabetes or CFRD. CFTR potentiator and corrector therapy has yet to demonstrate an effect on the rate of CFRD, but may improve insulin secretion. There is great opportunity for further research to better understand when and how best to treat glycaemic abnormalities in cystic fibrosis.
Topics: Cystic Fibrosis; Diabetes Mellitus; Humans; Hypoglycemic Agents; Insulin
PubMed: 31679720
DOI: 10.1016/j.jcf.2019.08.003 -
Journal of Cystic Fibrosis : Official... Nov 2017Pancreatic insufficiency (PI) affects about 85% of the cystic fibrosis population. Although most are PI soon after birth, some will have pancreatic sufficiency (PS) for... (Review)
Review
Pancreatic insufficiency (PI) affects about 85% of the cystic fibrosis population. Although most are PI soon after birth, some will have pancreatic sufficiency (PS) for some or all of their life. Understanding the clinical presentation, diagnosis, and management of PI is crucial to the care of people with cystic fibrosis.
Topics: Cystic Fibrosis; Disease Management; Exocrine Pancreatic Insufficiency; Humans
PubMed: 28986019
DOI: 10.1016/j.jcf.2017.06.011 -
Journal of Cystic Fibrosis : Official... Jul 2015Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the... (Review)
Review
Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the associated inflammation is both intense and ineffective at clearing pathogens. Persistent high-intensity inflammation leads to permanent structural damage of the CF airways and impaired lung function that eventually results in respiratory failure and death. Several defective inflammatory responses have been linked to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. The inflammation of the CF lung is dominated by neutrophils that release oxidants and proteases, particularly elastase. Neutrophil elastase in the CF airway secretions precedes the appearance of bronchiectasis, and correlates with lung function deterioration and respiratory exacerbations. Anti-inflammatory therapies are therefore of particular interest for CF lung disease but must be carefully studied to avoid suppressing critical elements of the inflammatory response and thus worsening infection. This review examines the role of inflammation in the pathogenesis of CF lung disease, summarizes the results of past clinical trials and explores promising new anti-inflammatory options.
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Cystic Fibrosis; Humans; Pneumonia
PubMed: 25814049
DOI: 10.1016/j.jcf.2015.03.003