Genome editing for the reproduction and remedy of human diseases in mice

Abstract

With the recent progress in genome-editing technologies, such as the CRISPR/Cas9 system, genetically modified animals carrying nucleotide substitutions or large chromosomal rearrangements can be produced rapidly and at low cost. Such genome-editing techniques have been applied in the generation of animal models, especially mice, for reproducing human disease mutations, such as single-nucleotide polymorphisms (SNPs) or large chromosomal rearrangements identified by genome-wide screening analyses. While application methods are under development for various complex mutations involving genome editing for mimicking human disease-causing mutations in mice, functional studies of mouse models carrying replicated human mutations are gradually being published. In this review, we discuss the recent progress in application methods of the CRISPR/Cas9 system, focusing on the production of mouse models of diseases.

Dominant negative Gfi1b mutations cause moderate thrombocytopenia and an impaired stress thrombopoiesis associated with mild erythropoietic abnormalities in mice

“…When modeling human mutations, including those that produce DN effects, the phenotypic consequences of those alleles may differ when translated into the mouse. 33 , 34 Here, we demonstrate that forms of GFI1B truncated at the fifth zinc finger had a DN effect in vitro similar to the analog human GFI1B mutations found in patients. 6 We also demonstrate that both murine short isoform 1 (GFI1B-p37) and long isoform 2 (GFI1B-p40) are not only able to repress target gene expression with an equivalent efficiency, but that they also can both act as DN alleles in a reporter gene assay when carrying the DN mutations.…”

Recent Advancements in Gene and Stem Cell‐Based Treatment Modalities: Potential Implications in Noise‐Induced Hearing Loss

“…Since genetics has been implicated in the pathophysiology of NIHL, recent advancements in genome editing can help in developing novel treatment modalities. Most notably, clustered, regularly interspaced, short palindromic repeat (CRISPR)/CRISPR‐associated nuclease (Cas9) technology is receiving much attention as the next generation of gene editing tools (Ahmad and Amiji, ; Demirci et al, ; Hara and Takada, ; Yan et al, ). Compared to conventional genome editing technologies, such as zinc finger nucleases (ZFNs) or transcriptional activator‐like effector nucleases (TALENs), CRISPR/Cas9 holds several advantages that make it enticing for application in hearing loss.…”

Model organism data evolving in support of translational medicine

“…Recently, genetic models that recapitulate symptoms of human disease have been developed, including the creation of or repair of mutations that mimic pathogenic human variants such as in retinitis pigmentosa 48 , mood disorders 49 and alpha1-antitrypsin deficiency 50 . Genome editing technologies allow for unprecedented precision in the types of mutations that can be introduced into different genetic backgrounds and are key to assessing functional significance of human genome variation 51–53 .…”