A sheep model of cystic fibrosis generated by CRISPR/Cas9 disruption of the CFTR gene

Fan, Zhiqiang; Périssé, Iuri Viótti; Cotton, Calvin U.; Regouski, Misha; Meng, Qinggang; Domb, Chaim; Wettere, Arnaud J. Van; Wang, Zhongde; Harris, Ann; White, Kenneth L.; Polejaeva, Irina A.

doi:10.1172/jci.insight.123529

Cited by 106 publications

(105 citation statements)

References 38 publications

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“…From 73 lambs born, 13 showed indel mutations (17.8%), and eight of them (61.5%) carried knock-in mutations by HDR (unpublished results). Also in sheep, researchers from Utah developed a knockout model for cystic fibrosis, a genetic disease with progressive lung affectation [62]. They combined CRISPR with SCNT to obtain CFTR e/e lambs with a similar phenotype as in humans, providing an interesting model to advance the development of new therapies.…”

Section: Large Animals Models In Research and Biomedicinementioning

confidence: 99%

CRISPR in livestock: From editing to printing

et al. 2020

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a b s t r a c tPrecise genome editing of large animals applied to livestock and biomedicine is nowadays possible since the CRISPR revolution. This review summarizes the latest advances and the main technical issues that determine the success of this technology. The pathway from editing to printing, from engineering the genome to achieving the desired animals, does not always imply an easy, fast and safe journey. When applied in large animals, CRISPR involves time-and cost-consuming projects, and it is mandatory not only to choose the best approach for genome editing, but also for embryo production, zygote microinjection or electroporation, cryopreservation and embryo transfer. The main technical refinements and most frequent questions to improve this disruptive biotechnology in large animals are presented. In addition, we discuss some CRISPR applications to enhance livestock production in the context of a growing global demand of food, in terms of increasing efficiency, reducing the impact of farming on the environment, enhancing pest control, animal welfare and health. The challenge is no longer technical. Controversies and consensus, opportunities and threats, benefits and risks, ethics and science should be reconsidered to enter into the CRISPR era.

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Section: Large Animals Models In Research and Biomedicinementioning

confidence: 99%

CRISPR in livestock: From editing to printing

et al. 2020

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“…Therefore, gene-edited ruminants might be useful for efficiently and cheaply producing large and complex bioactive proteins, small unstable peptides, and proteins that require extensive posttranslational modification and are multimeric in nature [85] . In addition to gene-edited animal models as bioreactors, both disease models of cystic fibrosis [87] and human hypophosphatasia [88] have been accomplished using CRISPR/Cas9 in sheep, which revealed characteristics consistent with disease symptoms observed in human patients and provided a novel large animal platform for human diseases.…”

Section: Discussionmentioning

confidence: 99%

The development and application of genome editing technology in ruminants: a review

Yuan¹,

Gao²,

Han³

et al. 2020

Front. Agr. Sci. Eng.

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Transgenic ruminants are a valuable resource for both animal breeding and biomedical research. The development of transgenic breeding is proceeding slowly, because it suffers from low efficiency of gene transfer and possible safety problems from uncontrolled random integration. However, new breeding methods combined with genome editing and somatic cell nuclear transfer or microinjection can offer an economic and efficient way to produce gene-edited ruminants, which can serve as bioreactors or have improved disease resistance, animal welfare and product quality. Recent advances in precise genome editing technologies, especially clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 nucleases, are enabling the systematic development of gene-edited ruminant production. This review covers the development of gene-edited ruminants, the particulars of site-specific engineered nucleases and the state of the art and new insights into practical applications and social acceptance of genome editing technology in ruminants. It is concluded that the production of gene-edited ruminants is feasible and through improvements in genome editing technology it is possible to help feed the world.

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“…NHPs, minipigs, and sheep all remain viable options as large animals to model HD, and species choice should be considered on their strengths and weaknesses. Minipigs have the largest litters with the shortest gestation time, but sheep models have faithfully reproduced other human neurological conditions (CLN1, Tay-Sachs, Cystic fibrosis) [ 80 – 83 ] and are amenable to neurological and behavioral testing. The extant KI-HD-85Q and TgHD (N548) minipigs and transgenic (OVT73) sheep are certainly appropriate for early-stage PK-PD-safety and possibly biomarker testing, even without a fully manifest behavioral phenotype.…”

Section: Sheep Modelsmentioning

confidence: 99%

Large Animal Models of Huntington’s Disease: What We Have Learned and Where We Need to Go Next

Howland

Ellederová

Aronin

et al. 2020

JHD

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Genetically modified rodent models of Huntington’s disease (HD) have been especially valuable to our understanding of HD pathology and the mechanisms by which the mutant HTT gene alters physiology. However, due to inherent differences in genetics, neuroanatomy, neurocircuitry and neurophysiology, animal models do not always faithfully or fully recapitulate human disease features or adequately predict a clinical response to treatment. Therefore, conducting translational studies of candidate HD therapeutics only in a single species (i.e. mouse disease models) may not be sufficient. Large animal models of HD have been shown to be valuable to the HD research community and the expectation is that the need for translational studies that span rodent and large animal models will grow. Here, we review the large animal models of HD that have been created to date, with specific commentary on differences between the models, the strengths and disadvantages of each, and how we can advance useful models to study disease pathophysiology, biomarker development and evaluation of promising therapeutics.

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A sheep model of cystic fibrosis generated by CRISPR/Cas9 disruption of the CFTR gene

Cited by 106 publications

References 38 publications

CRISPR in livestock: From editing to printing

CRISPR in livestock: From editing to printing

The development and application of genome editing technology in ruminants: a review

Large Animal Models of Huntington’s Disease: What We Have Learned and Where We Need to Go Next

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