Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward

Cooney, Ashley L.; McCray, Paul B.; Sinn, Patrick L.

doi:10.3390/genes9110538

Cited by 106 publications

(82 citation statements)

References 214 publications

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“…Gene therapies that utilize viral delivery vehicles have been reviewed. 38 One such approach, which is agnostic to genotype, is to use mRNA to replace CFTR protein. A second approach is to use mRNA encoding for CRISPR-based gene editors to edit genomic DNA in target cells.…”

Section: Rna Therapies Can Be Used To Replace or Edit Cftrmentioning

confidence: 99%

Treating Cystic Fibrosis with mRNA and CRISPR

et al. 2020

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Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory, they can silence or edit any gene by encoding CRISPR nucleases, or alternatively, produce any missing protein. Yet not all mRNA therapies are equally likely to succeed. Over the past several years, an increasing number of clinical trials with siRNA-and antisense oligonucleotide-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by nonviral systems. First, scientists have come to understand that some genes make better targets for RNA therapies than others. Second, scientists have learned that the type and position of chemical modifications made to an RNA drug can alter its therapeutic window, toxicity, and bioavailability. Third, scientists have found that safe and targeted drug delivery vehicles are required to ferry mRNA therapies into diseased cells. In this study, we apply these learnings to cystic fibrosis (CF). We also describe lessons learned from a subset of CF gene therapies that have already been tested in patients. Finally, we highlight the scientific advances that are still required for nonviral mRNA-or CRISPR-based drugs to treat CF successfully in patients.

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Section: Rna Therapies Can Be Used To Replace or Edit Cftrmentioning

confidence: 99%

Treating Cystic Fibrosis with mRNA and CRISPR

et al. 2020

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“…For several years, different therapeutic strategies have been identified to improve the efficiency of CF treatment. Various gene-based and non-gene-based therapeutics have proven to be promising approaches for the treatment of CF [176][177][178][179]. Despite the enormous developments in the management and treatment of CF in recent years, several challenges still exist.…”

Section: Nanocarriers For Cf Treatmentmentioning

confidence: 99%

Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies

et al. 2020

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Cystic Fibrosis (CF), an autosomal recessive genetic disease, is caused by a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). This mutation reduces the release of chloride ions (Cl−) in epithelial tissues, and hyperactivates the epithelial sodium channels (ENaC) which aid in the absorption of sodium ions (Na+). Consequently, the mucus becomes dehydrated and thickened, making it a suitable medium for microbial growth. CF causes several chronic lung complications like thickened mucus, bacterial infection and inflammation, progressive loss of lung function, and ultimately, death. Until recently, the standard of clinical care in CF treatment had focused on preventing and treating the disease complications. In this review, we have summarized the current knowledge on CF pathogenesis and provided an outlook on the current therapeutic approaches relevant to CF (i.e., CFTR modulators and ENaC inhibitors). The enormous potential in targeting bacterial biofilms using antibiofilm peptides, and the innovative therapeutic strategies in using the CRISPR/Cas approach as a gene-editing tool to repair the CFTR mutation have been reviewed. Finally, we have discussed the wide range of drug delivery systems available, particularly non-viral vectors, and the optimal properties of nanocarriers which are essential for successful drug delivery to the lungs.

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“…16,17 However, early hopes for fast delivery of new gene-addition treatments to CF patients had to be calmed as the challenges associated with barriers to gene vector delivery to the CF airway epithelium, including inflammation and immune responses, and adverse events in gene therapy trials became clearer. 18 For many years gene therapy-not just for CF, but for many inherited diseaseslay in the translational ''valley of death.'' 19 Despite more than 30 years of development since the CFTR gene was discovered, and after at least 36 gene therapy clinical trials or studies, none of these methods has yet been approved clinically for treatment of CF lung disease.…”

Section: Cf Gene Therapymentioning

confidence: 99%

Will Airway Gene Therapy for Cystic Fibrosis Improve Lung Function? New Imaging Technologies Can Help Us Find Out

Parsons

Donnelley

2020

Human Gene Therapy

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The promise of genetic therapies has turned into reality in recent years, with new first-line treatments for fatal diseases now available to patients. The development and testing of genetic therapies for respiratory diseases such as cystic fibrosis (CF) has also progressed. The addition of gene editing to the genetic agent toolbox, and its early success in other organ systems, suggests we will see rapid expansion of gene correction options for CF in the future. Although substantial progress has been made in creating techniques and genetic agents that can be highly effective for CF correction in vitro, physiologically relevant functional in vivo changes have been largely prevented by poor delivery efficiency within the lungs. Somewhat hidden from view, however, is the absence of reliable, accurate, detailed, and noninvasive outcome measures that can detect subtle disease and treatment effects in the lungs of humans or animal models. The ability to measure the fundamental function of the lung-ventilation, the effective transport of air throughout the lung-has been constrained by the available measurement technologies. Without sensitive measurement methods, it is difficult to quantify the effectiveness of genetic therapies for CF. The mainstays of lung health assessment are spirometry, which cannot provide adequate disease localization and is not sensitive enough to detect small early changes in disease; and computed tomography, which provides structural rather than functional information. Magnetic resonance imaging using hyperpolarized gases is increasingly useful for lung ventilation assessment, and it removes the radiation risk that accompanies X-ray methods. A new lung imaging technique, X-ray velocimetry, can now offer highly detailed regional lung ventilation information well suited to the diagnosis, treatment, and monitoring needs of CF lung disease, particularly after the application of genetic therapies. In this review, we discuss the options now available for imaging-based lung function measurement in the generation and use of genetic and other therapies for treating CF lung disease.

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Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward

Cited by 106 publications

References 214 publications

Treating Cystic Fibrosis with mRNA and CRISPR

Treating Cystic Fibrosis with mRNA and CRISPR

Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies

Will Airway Gene Therapy for Cystic Fibrosis Improve Lung Function? New Imaging Technologies Can Help Us Find Out

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