Abstract
PurposeCRISPR gene-editing technology has the potential to transform the diagnosis and treatment of infectious diseases, but most clinicians are unaware of its broad applicability. Derived from an ancient microbial defence system, these so-called “molecular scissors” enable precise gene editing with a low error rate. However, CRISPR systems can also be targeted against pathogenic DNA or RNA sequences. This potential is being combined with innovative delivery systems to develop new therapeutic approaches to infectious diseases.MethodsWe searched Pubmed and Google Scholar for CRISPR-based strategies in the diagnosis and treatment of infectious diseases. Reference lists were reviewed and synthesized for narrative review.ResultsCRISPR-based strategies represent a novel approach to many challenging infectious diseases. CRISPR technologies can be harnessed to create rapid, low-cost diagnostic systems, as well as to identify drug-resistance genes. Therapeutic strategies, such as CRISPR systems that cleave integrated viral genomes or that target resistant bacteria, are in development. CRISPR-based therapies for emerging viruses, such as SARS-CoV-2, have also been proposed. Finally, CRISPR systems can be used to reprogram human B cells to produce neutralizing antibodies. The risks of CRISPR-based therapies include off-target and on-target modifications. Strategies to control these risks are being developed and a phase 1 clinical trials of CRISPR-based therapies for cancer and monogenic diseases are already underway.ConclusionsCRISPR systems have broad applicability in the field of infectious diseases and may offer solutions to many of the most challenging human infections.
Highlights
The discovery of CRISPR “Clustered regularly interspaced palindromic repeats” (CRISPR) were first discovered in the archaea species, Haloferax mediterranei, by a Spanish microbiologist, Dr Francisco Mojica, They comprised palindromic sequences of 30 base pairs interspersed with spacer sequences of 36 bp [1]
The discovery did not generate interest outside the field of microbiology, when similar palindromic repeats were identified in multiple bacterial species, including Escherichia coli, Mycobacterium tuberculosis, and Clostridium difficile [2], it became apparent that CRISPR repeats might serve an important conserved function
Mojica postulated that CRISPR sequences and their associated Cas proteins might function as a microbial defense system, storing “memories” of bacteriophages, which could be used to fight subsequent infections [1, 3]
Summary
The discovery of CRISPR “Clustered regularly interspaced palindromic repeats” (CRISPR) were first discovered in the archaea species, Haloferax mediterranei, by a Spanish microbiologist, Dr Francisco Mojica, They comprised palindromic sequences of 30 base pairs (bp) interspersed with spacer sequences of 36 bp [1]. His work was based on the groundbreaking studies of Emmanuelle Charpentier and Jennifer Doudna, who had previously identified the key elements required for CRISPR-mediated cleavage [7] Zhang and his team recognized the potential of CRISPR systems to produce highly targeted modifications in human genes and designed a method to express guide RNAs (the equivalent of the crRNAs), tracrRNA, and the Cas cleavage protein in human cells [6]. CCR5 ablation was confirmed in a percentage of the patient’s T cells after engraftment and whole genome sequencing showed no evidence of off-target effects Another small phase 1 trial included 3 patients with refractory cancer (two with advanced myeloma and one with liposarcoma) whose T cells were harvested, modified using CRISPR engineering to express a T cell receptor specific to the NYESO-1 tumor antigen, and reintroduced into the patients [13]. As safety issues are addressed, the feasibility of using CRISPR therapeutics in human patients with infectious diseases will only increase
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