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

Abstract

Respiratory diseases, such as influenza infection, acute tracheal bronchitis, pneumonia, tuberculosis, chronic obstructive pulmonary disease, asthma, lung cancer and nasopharyngeal carcinoma, continue to significantly impact human health. Diseases of the lung and respiratory tract are influenced by environmental conditions and socio-economic factors; however, many of these serious respiratory disorders are also rooted in genetic or epigenetic causes. Clustered regularly interspaced palindromic repeats (CRISPR) and CRISPRassociated (Cas) proteins, isolated from the immune system of prokaryotes, provide a tool to manipulate gene sequences and gene expression with significant implications for respiratory research. CRISPR/Cas systems allow preclinical modelling of causal factors involved in many respiratory diseases, providing new insights into their underlying mechanisms. CRISPR can also be used to screen for genes involved in respiratory processes, development and pathology, identifying novel disease drivers or drug targets. Finally, CRISPR/-Cas systems can potentially correct genetic mutations and edit epigenetic marks that contribute to respiratory disorders, providing a form of personalized medicine that could be used in conjunction with other technologies such as stem cell reprogramming and transplantation. CRISPR gene editing is a young field of research, and concerns regarding its specificity, as well as the need for efficient and safe delivery methods, need to be addressed further. However, CRISPR/Cas systems represent a significant step forward for research and therapy in respiratory health, and it is likely we will see the breakthroughs generated from this technology continue.

‘Omics’: The new language in medicine that we all must learn

“…CRISPR/Cas system in Streptococcus pyogenes can be used to remove genes from DNA in a process called ‘gene editing’ as reviewed by Moses et al . This technique may remove pathogenic genes in certain diseases but also be used to model diseases …”

CRISPR‐Cas9 technology: A new direction for personalized medicine in respiratory disease?

“…Until recently, gene editing techniques were limited to protein‐driven systems that are often time‐consuming and expensive. The invited review by Moses and Kaur, in this issue of Respirology, explains the origin and mechanisms of a novel RNA‐guided gene editing system, discovered in bacteria, called CRISPR. CRISPR stands for ‘clustered regularly interspaced short palindromic repeats’.…”

“…As elegantly outlined by Moses and Kaur, researchers have exploited this bacterial immune system to alter the eukaryotic genome. The most characterized CRISPR‐Cas system is the CRISPR‐Cas9 system, which is comprised of the Cas9 nuclease and the crRNA and is found in Streptococcus pyogenes .…”

“…The CRISPR‐Cas9 system is potentially highly compatible with gene therapies targeting monogenetic diseases such as cystic fibrosis (CF). As described in the review, the CRISPR‐Cas9 system has been used to cleave the dysfunctional Cystic fibrosis transmembrane conductance regulator (CFTR) gene in an intestinal epithelial organoid model and insert a DNA template of the ‘corrected’ gene. The corrected gene was later shown to be expressed and fully functional …”

“…Whether being used for in vitro experiments or clinical applications, a number of challenges to the implementation of CRISPR‐Cas systems first need to be overcome. Moses and Kaur have given us important insights into these technical and biological issues, including accuracy and efficiency of the gene editing process (to avoid mismatches and off‐target effects), how to effectively deliver treated cells back to the body (as an innovative approach to intervention) and unintended consequences of gene editing of cells (such as activation of cellular responses to DNA damage, leading to cell death). Intensive research efforts are underway to overcome these barriers to further develop the suitability of CRISPR gene editing systems for biological and clinical applications.…”