Editorial: Genome Editing to Treat Cystic Fibrosis and Other Pulmonary Diseases.
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ABSTRACT:
SUBMITTER: Vaidyanathan S
PROVIDER: S-EPMC9218674 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Liver has a central role in protein and lipid metabolism, and diseases involving hepatocytes have often repercussions on multiple organs and systems. Hepatic disorders are frequently characterized by production of defective or non-functional proteins, and traditional gene therapy approaches have been attempted for years to restore adequate protein levels through delivery of transgenes. Recently, many different genome editing platforms have been developed aimed at correcting at DNA level the defects underlying the diseases. In this Review we discuss the latest applications of these tools applied to develop therapeutic strategies for rare liver disorders, in particular updating the literature with the most recent strategies relying on base editors technology.
| S-EPMC7063531 | biostudies-literature
Project description:Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the CFTR gene. There are at least 346 disease-causing variants in the CFTR gene, but effective small-molecule therapies exist for only ~10% of them. One option to treat all mutations is CFTR cDNA-based therapy, but clinical trials to date have only been able to stabilise rather than improve lung function disease in patients. While cDNA-based therapy is already a clinical reality for a number of diseases, some animal studies have clearly established that precision genome editing can be significantly more effective than cDNA addition. These observations have led to a number of gene-editing clinical trials for a small number of such genetic disorders. To date, gene-editing strategies to correct CFTR mutations have been conducted exclusively in cell models, with no in vivo gene-editing studies yet described. Here, we highlight some of the key breakthroughs in in vivo and ex vivo gene and base editing in animal models for other diseases and discuss what might be learned from these studies in the development of editing strategies that may be applied to cystic fibrosis as a potential therapeutic approach. There are many hurdles that need to be overcome, including the in vivo delivery of editing machinery or successful engraftment of ex vivo-edited cells, as well as minimising potential off-target effects. However, a successful proof-of-concept study for gene or base editing in one or more of the available CF animal models could pave the way towards a long-term therapeutic strategy for this disease.
| S-EPMC6562706 | biostudies-literature
Project description:Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The 3272-26A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene, generating new acceptor and donor splice sites respectively. Here we develop a genome editing approach to permanently correct these genetic defects, using a single crRNA and the Acidaminococcus sp. BV3L6, AsCas12a. This genetic repair strategy is highly precise, showing very strong discrimination between the wild-type and mutant sequence and a complete absence of detectable off-targets. The efficacy of this gene correction strategy is verified in intestinal organoids and airway epithelial cells derived from CF patients carrying the 3272-26A>G or 3849+10kbC>T mutations, showing efficient repair and complete functional recovery of the CFTR channel. These results demonstrate that allele-specific genome editing with AsCas12a can correct aberrant CFTR splicing mutations, paving the way for a permanent splicing correction in genetic diseases.
| S-EPMC6685978 | biostudies-literature
Project description:Although cystic fibrosis (CF) is the most common inherited respiratory disease, the burden of influenza among individuals with CF is not well characterized.We used the CF Foundation Patient Registry to determine the relationship between pulmonary exacerbation incidence rate and influenza virus season from July 2003 through June 2007. The outcome of interest, pulmonary exacerbation, was defined as treatment of a respiratory illness with IV antibiotics. Each influenza season was defined as all months during which >/= 15% of laboratory tests for influenza virus were positive in the US influenza virologic surveillance system. We calculated incidence rates of pulmonary exacerbation during the influenza and summertime seasons as well as relative rates with 95% CIs. A multivariate regression model adjusted for demographic and clinical predictors.In 2003, the patient cohort size was 21,506 patients, and 7,727 patients experienced at least one pulmonary exacerbation. The overall pulmonary exacerbation incidence rate in the influenza season was 595.0 per 10,000 person-months compared with a summertime baseline of 549.6 per 10,000 person-months. The incidence rate ratio was 1.08 (95% CI: 1.06, 1.10). Multivariate analysis did not change our estimate of risk (adjusted odds ratio: 1.07; 95% CI: 1.05, 1.10). An estimated annual excess of 147.6 per 10,000 person-months or an excess 2.1% of total exacerbations occur during the influenza season.Our data demonstrate a substantial contribution of the influenza season to CF morbidity. Further studies to determine any causal link between influenza infection and CF pulmonary exacerbations are necessary.
| S-EPMC2851556 | biostudies-other
Project description:RationaleIndividuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life.ObjectivesThe goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects.MethodsWe conducted a multicenter, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbation and contacted participants to determine if treatment for acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms.Measurements and main resultsThe primary outcome was the 52-week change in FEV1. Secondary outcomes included time to first exacerbation and subsequent exacerbation, quality of life, and change in weight. A total of 267 patients were randomized, and the study arms were well matched at baseline. There was no significant difference between study arms in 52-week mean change in FEV1 slope (mean slope difference, 0.00 L, 95% confidence interval, -0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms.ConclusionsAn intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT01104402).
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Project description: Not available
| S-EPMC8720958 | biostudies-literature
Project description:Development of genome editing methods created new opportunities for the development of etiology-based therapies of hereditary diseases. Here, we demonstrate that CRISPR/Cas9 can correct p.F508del mutation in the CFTR gene in the CFTE29o- cells and induced pluripotent stem cells (iPSCs) derived from patients with cystic fibrosis (CF). We used several combinations of Cas9, sgRNA and ssODN and measured editing efficiency in the endogenous CFTR gene and in the co-transfected plasmid containing the CFTR locus with the p.F508del mutation. The non-homologous end joining (NHEJ) frequency in the CFTR gene in the CFTE29o- cells varied from 1.25% to 2.54% of alleles. The best homology-directed repair (HDR) frequency in the endogenous CFTR locus was 1.42% of alleles. In iPSCs, the NHEJ frequency in the CFTR gene varied from 5.5% to 12.13% of alleles. The best HDR efficacy was 2.38% of alleles. Our results show that p.F508del mutation editing using CRISPR/Cas9 in CF patient-derived iPSCs is a relatively rare event and subsequent cell selection and cultivation should be carried out.
| S-EPMC7657551 | biostudies-literature
Project description: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.
| S-EPMC7528649 | biostudies-literature
Project description:Nonsense-mediated decay (NMD) is a major pathogenic mechanism underlying a diversity of genetic disorders. Nonsense variants tend to lead to more severe disease phenotypes and are often difficult targets for small molecule therapeutic development as a result of insufficient protein production. The treatment of cystic fibrosis (CF), an autosomal recessive disease caused by mutations in the CFTR gene, exemplifies the challenge of therapeutically addressing nonsense mutations in human disease. Therapeutic development in CF has led to multiple, highly successful protein modulatory interventions, yet no targeted therapies have been approved for nonsense mutations. Here, we have designed a CRISPR-Cas9-based strategy for the targeted prevention of NMD of CFTR transcripts containing the second most common nonsense variant listed in CFTR2, W1282X. By introducing a deletion of the downstream genic region following the premature stop codon, we demonstrate significantly increased protein expression of this mutant variant. Notably, in combination with protein modulators, genome editing significantly increases the potentiated channel activity of W1282X-CFTR in human bronchial epithelial cells. Furthermore, we show how the outlined approach can be modified to permit allele-specific editing. The described approach can be extended to other late-occurring nonsense mutations in the CFTR gene or applied as a generalized approach for gene-specific prevention of NMD in disorders where a truncated protein product retains full or partial functionality.
| S-EPMC7256445 | biostudies-literature
Project description:There is growing evidence that the great phenotypic variability in patients with cystic fibrosis (CF) not only depends on the genotype, but apart from a combination of environmental and stochastic factors predominantly also on modifier gene effects. It has been proposed that genes interacting with CF transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) are potential modifiers. Therefore, we assessed the impact of single-nucleotide polymorphisms (SNPs) of several of these interacters on CF disease outcome. SNPs that potentially alter gene function were genotyped in 95 well-characterized p.Phe508del homozygous CF patients. Linear mixed-effect model analysis was used to assess the relationship between sequence variants and the repeated measurements of lung function parameters. In total, we genotyped 72 SNPs in 10 genes. Twenty-five SNPs were used for statistical analysis, where we found strong associations for one SNP in PPP2R4 with the lung clearance index (P ≤ 0.01), the specific effective airway resistance (P ≤ 0.005) and the forced expiratory volume in 1 s (P ≤ 0.005). In addition, we identified one SNP in SNAP23 to be significantly associated with three lung function parameters as well as one SNP in PPP2R1A and three in KRT19 to show a significant influence on one lung function parameter each. Our findings indicate that direct interacters with CFTR, such as SNAP23, PPP2R4 and PPP2R1A, may modify the residual function of p.Phe508del-CFTR while variants in KRT19 may modulate the amount of p.Phe508del-CFTR at the apical membrane and consequently modify CF disease.
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