Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique

Abstract

One of the most revolutionary technologies in recent years in the field of molecular biology is CRISPR-Cas9. CRISPR technology is a promising tool for gene editing that provides researchers the opportunity to easily alter DNA sequences and modify gene function. Its many potential applications include correcting genetic defects, treating and preventing the spread of diseases. Cystic fibrosis (CF) is one of the most common lethal genetic diseases caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although CF is an old acquaintance, there is still no effective/resolutive cure. Life expectancy has improved thanks to the combination of various treatments, but it is generally below average. Recently, a significant number of additional key medications have become licensed in Europe for the CF treatment including CFTR modulators. But innovative genomically-guided therapies have begun for CF and it is predictable that this will lead to rapid improvements in CF clinical disease and survival in the next decades. In this way, CRISPR-Cas9 approach may represent a valid tool to repair the CFTR mutation and hopeful results were obtained in tissue and animal models of CF disease.

An Overview of the Homozygous Cystic Fibrosis Transmembrane Conductance Regulator Mutation c.3700 A>G (p.Ile1234Val) in Qatar

“…Areas for future research include testing of the CFTR transcript and activity levels in different samples including nasal cells and organoids [39•] among patients with the CFTR I1234V mutation, as studies have shown that organoids may be used for the development of personalized treatment for patients with CF [40•, 41•]. Applying Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology as a tool for gene editing along with its promising results as shown elsewhere on other mutations [2] is yet to take place for the CFTR I1234V mutation. In conclusion, a better future for CF patients worldwide and locally in Qatar is contingent upon intensifying research efforts and expanding on current collaborations.…”

“…The cause is a mutation in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein [1]. The number of CFTR gene mutations exceeds 2000 so far [2]. CF involves the presence of two disease-causing mutations on two separate chromosomes [3].…”

Applications of CRISPR systems in respiratory health: Entering a new ‘red pen’ era in genome editing

“…While systemic delivery of pharmacological agents is successful for many conditions, the targeting of genetic therapies via systemic administration is only likely to be feasible if there are bone marrow precursors of the cellular target, or a method to preferentially deliver a systemically administered agent to lung tissues. In the case of CF, intravenous delivery would only reach the alveolar surface of the lung and not the surface epithelium of the bronchioles where CFTR is expressed …”

“…Direct delivery to the lung via aerosol or direct intratracheal instillation might be a feasible alternative to systemic administration. However, these approaches also have many challenges, particularly in the presence of significant heterogeneous disease expression, airway mucus, mucociliary clearance and immune responses . For example, structural lung abnormalities in CF patients are known to influence the deposition patterns of inhaled therapeutic agents, resulting in an impaired effect of treatment .…”

“…An alternative strategy to restrict genetic modifications to the intended cell type is to conduct gene editing ex vivo. There are exciting possibilities for cell transplantation strategies to treat congenital respiratory diseases, for example by taking iPSC or bronchioalveolar stem cells from the lung, engineering them with CRISPR to correct a genetic defect and transplanting them back into the stem cell niche in the lung . However, the transplantation of cells raises its own set of challenges, and it is uncertain whether CRISPR‐edited cells could be successfully reconstituted and maintained in the respiratory environment.…”