Insight to approaches of gene therapy on cystic fibrosis Review article
Insight to approaches of gene therapy on cystic fibrosis Review article
Fatemeh Moghaddam,1Saman Hakimian,2,*
1. Graduated Student from Islamic Azad University Of Tehran Varamin Pishva Branch 2. M.sc student of Pathogenic Microbes Islamic Azad University Central Tehran Branch
Introduction: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane regulator(CFTR), a cyclic AMP-activated chloride channel. Mutations in CFTR lead to imbalanced water and ion movement across the airway epithelium, resulting in thichened mucus, chronic bacterial infection and inflammation, with progressive loss of pulmonary function. CFTR modulators offer therapeutic opportunities for a wide range of CFTR mutation, which should enable treatment for approximately 90% of CF patients. CF gene therapy clinical trials by delivery of CFTR performed with Adeno-associated virus (AAV) and adenovirus, as well as non-viral liposome formulations continue to offer promise but so far have not led to the hoped-for clinical breakthroughs that this upproach offers.
Gene therapy is an attractive strategy for CF lung disease because it treats the underlying cause of the disease rather than its symptoms. While gene correction showed limited success in both cell and animal models, therapy for patients had proven to be more difficult. In-vitro studies have suggested that not all cells need to express normal CFTR to effect normal epithelial functions. In a mixing experiment where normal cells were mixed with CF mutant cells, only 6-10% of the epithelium needed to contain epithelia cells expressing normal CFTR to restore chloride transport similar to normal epithelia. Conversely, in a gene targeting study, up to 25% gene correction could restore mucus transport in homozygous F508del human airway epithelial cells. The number of cells harboring wide-type CFTR that is needed to translate into clinical benefit in patience remains unknown. However, theoretically correcting a stem cell population within the airways may provide a renewable and long-term source of endogenous cells capable of renewing the damaged epithelia with cells that express wild-type CFTR.
There are no other clinical trials for CF gene therapy.
Methods: There are several gene delivery methods to introduce a therapeutic gene or gene targeting. Both non-viral and viral delivery vectors have been tested in CF gene therapy research. (i) Non-viral vectors: Non-viral vectors were developed as a strategy to deliver the CFTR gene. These non-integrating gene delivery methods do not disrupt the host genome and thus the risk of causing mutagenesis are low. Non-viral vectors are not restricted in the cargo load enabling larger donor DNA fragments to be used for gene repair. However, the efficacy of gene delivery is comparatively lower than viral methods. To enhance gene transfer into the nucleus, a cationic lipid is used to formulate the plasmid DNA complexed with CFTR enhanced chloride transport by 20% in CF patients compared to non-CF levels. Using a nebulized cationic lipid pGM169/GL67A to deliver the donor DNA, up to 3.7% increase in CFTR function in the lungs of CF patients was observed.
Results: Gene therapy for cystic fibrosis will mean a completely different disease and life perspective for many patients. New approaches need to be pursued to propose a disease-modifying treatment for all patients. For those who bear rare mutations that might be responsive to current CFTR modulators, new ways of evaluating drugs in very scarce population are worked on.
Conclusion: an effective therapy to treat all CF remains a challenge. While the discoveries of new small molecule modulators have greatly advanced treatment for some CF, the Since the discovery of the CF gene over 30 years ago, it has become apparent that finding effectiveness of these lifesaving drugs have not been universally effective and rather limited to specific classes of mutations. Rare CFTR variants remain uncured. Now, with recent advances in new gene editing tools, and new animal models, new precise gene targeting methods to treat CF disease will emerge and lead to potential effective personalized therapies. With new advancements in gene editing technologies coupled with advanced cell models to test gene engineering approaches, this will lead to rapid developments of new therapies for all CF.