Increasing the Efficiency of Drug Discovery by Combining Zebrafish and CRISPR/Cas9

CRISPR or “Clustered Regularly Interspaced Short Palindromic Repeats,” is a simple yet powerful tool for editing genomes. It allows researchers to alter DNA sequences and modify gene function easily.

Zebrafish is a small freshwater fish that has been used for decades as a classical developmental biology research model. The zebrafish specific characteristics such as a large number of progeny and external development of the larvae, fast life cycle, small size, and transparency allowed performing large-scale genetic screenings, which would have been unattainable in mammalian models. Nowadays, research in zebrafish has expanded from basic research toward most translational biomedical areas. Several facts suggest that the broader use of zebrafish could benefit the biomedical community in streamlining the drug discovery process. In that sense, regulatory agencies recommend the use of this and other small animals. Studies show how using zebrafish predicts toxicity liabilities for more than 80% of the drugs. Regarding biologic translatability, we stated above the high conservation in genes, protein structure, and physiology with humans. To further prove the applicability of the zebrafish model during the drug discovery process, an important step would be the development of humanized zebrafish models, in which native genes would be exchanged by their human orthologues, therefore, recapitulating same biological pathways but with an intact human target protein structure. Despite some challenges, zebrafish is a very suitable and reliable experimental model for performing phenotypic drug discovery. In fact, the use of zebrafish is already helping the pharmaceutical industry on three different fronts. CRISPR or “Clustered Regularly Interspaced Short Palindromic Repeats,” is a simple yet powerful tool for editing genomes. It allows researchers to alter DNA sequences and modify gene function easily. Its many potential applications include correcting genetic defects, treating and preventing the spread of diseases, and improving crops. CRISPRs are specialized stretches of DNA. The protein Cas9 (or "CRISPR-associated") is an enzyme that acts like a pair of molecular scissors capable of cutting strands of DNA. CRISPR/Cas9 is a system that allows rapid and accurate genome editing, has become the most widespread technique in zebrafish and other model systems. “CRISPRs” is a specialized region of DNA with two distinct characteristics: the presence of nucleotide repeats and spacers. Repeated sequences of nucleotides (the building blocks of DNA) are distributed throughout a CRISPR region. Spacers are bits of DNA that are interspersed among these repeated sequences. The CRISPR/Cas9 experimental basics and general applications have been reviewed extensively. It is important to reiterate some essential details relevant to this review. All gene-editing methods, including CRISPR/Cas9, are based on the inherent capability of cells to repair their genome after DNA DSB or “Double-Strand Break” events. At ZeClinics, we provide expertise in transgenic manipulation and zebrafish biology for generating mutant lines and later phenotype them, to use them for custom drug screenings. Contact us for your biological/pharmacological question, and we will propose and run the best zebrafish-based scientific methodology and will provide you with reliable results.

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