Gene Editing in Rabbits: Unique Opportunities for Translational Biomedical Research

Xu, Jie; Zhang, Jifeng; Yang, Dongshan; Song, Jun; Pallas, Brooke; Zhang, Chen; Hu, Jiafen; Peng, Xuwen; Christensen, Neil D.; Han, Renzhi; Chen, Y. Eugene

doi:10.3389/fgene.2021.642444

Cited by 10 publications

(8 citation statements)

References 120 publications

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“…The larger models, CF pigs and sheep, manifest liver phenotypes ( 24 , 25 ) but are not easily adoptable to a conventional animal research setting. On the other hand, rabbit is a classic model species ( 59 ) that is routinely used in most research institutes. Although smaller than pigs and ferrets, rabbits are much larger than the rodents, hence would allow some otherwise inhibitory procedures/measurements, for example liver ultrasound exam, to be conducted in CF rabbits, that should be considered another advantage of this model.…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Hou

Song

et al. 2022

PNAS Nexus

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Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting multiple organs. Approximately 30% CF patients develop CF-related liver disease (CFLD), which is the third most common cause of morbidity and mortality of CF. CFLD is progressive, and many of the severe forms eventually need liver transplantation. The mechanistic studies and therapeutic interventions to CFLD are unfortunately very limited. Utilizing the CRISPR/Cas9 technology, we recently generated CF rabbits by introducing mutations to the rabbit cystic fibrosis transmembrane conductance regulator (CFTR) gene. Here we report the liver phenotypes and mechanistic insights into the liver pathogenesis in these animals. CF rabbits develop spontaneous hepatobiliary lesions and abnormal biliary secretion accompanied with altered bile acid profiles. They exhibit non-alcoholic steatohepatitis (NASH)-like phenotypes, characterized by hepatic inflammation, steatosis, and fibrosis, as well as altered lipid profiles and diminished glycogen storage. Mechanistically, our data reveal that multiple stress-induced metabolic regulators involved in hepatic lipid homeostasis were up-regulated in the livers of CF-rabbits, and that endoplasmic reticulum (ER) stress response mediated through IRE1α-XBP1 axis as well as NF-κB- and JNK-mediated inflammatory responses prevail in CF rabbit livers. These findings show that CF rabbits manifest many CFLD-like phenotypes and suggest targeting hepatic ER stress and inflammatory pathways for potential CFLD treatment.

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Section: Discussionmentioning

confidence: 99%

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Hou

Song

et al. 2022

PNAS Nexus

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“…Compared with large animals such as cattle or goat, it has the advantages of more ovulation, short pregnancy, strong fecundity and more estrus throughout the year. Compared with mice, it has the advantages of high lactation and suitable for the production of recombinant medical proteins, which can fill the "blank" between large and small animals [16,37] . The rhPA single transgenic rabbits (goat β-casein gene as the regulatory sequence and verified expression) were selected as the donor rabbits [16] , and 151 fertilized eggs were obtained by superovulation via FSH/hCG.…”

Section: Discussionmentioning

confidence: 99%

The High-Level Expression Analysis of RhPA In The RhPA/gGH Double-Transgenic Rabbits And Its Thrombolysis Activity In Vitro

Song

Luo

et al. 2022

Preprint

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Objective: In this study, the rhPA/gGH double transgenic rabbits were constructed, and the expression level of rhPA,rabbit growth and development features were analyzed, which might provide a new idea for obtain rhPA high level expression transgenic animals.Method: Two rhPA transgenic rabbits fertilized eggs were microinjected with linearized GH plasmid to obtain the rhPA/gGH rabbits.The integration of rhPA/gGH gene was detected by PCR. The rhPA expression level in transgenic rabbit milk was detected by ELISA and Western blotting,and FAPA was performed to detect the in vitro thrombolytic activity of rhPA.The body weight of transgenic rabbits at different growth stages were measured to test the effect of gGH gene on rhPA/gGH double transgenic rabbits growth and development .Result: A total of 151 rhPA transgenic rabbits fertilized eggs were obtained through superovulation, 125 of them were microinjected with linearized GH plasmid and transplanted into 8 surrogate mother rabbits.Six surrogate mother rabbits were pregnant, with a pregnancy rate of 75.0% (6/8)，16 rhPA/gGH gene double transgenic rabbits were identified by PCR (10♂,6♀). The rhPA expression levels in rhPA single-transgenic rabbit whey were 0.27–0.63g/L, while the rhPA expression leves were 4.98-12.24 g/L in the rhPA/gGH double-transgenic rabbits whey. The rhPA expression levels of rhPA/gGH double-transgenic rabbit whey were significantly increased by about 17.2–23.8 times, and had higher thrombolytic activity in vitro. There was no significant difference in body weight between rhPA/gGH double transgenic rabbits, rhPA single transgenic or non-transgenic rabbits from birthday to 10 months age(P>0.05). Conclusion: The rhPA/gGH double transgenic rabbits were successfully constrected, which was proved that the introduction of gGH gene could significantly increase the rhPA expression level in the milk of transgenic rabbits and without affecting the growth and development of transgenic rabbits, which laid a foundation for the preparation of transgenic rabbits with higher recombinant protein expression level in the future, and also provide new ideas and new methods for the establishment of mammary gland bioreactor.

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“…This system and its variants can efficiently mediate knock-in and knockout of targeted genes and are thus widely used in the genome-editing of different species ( Ma et al, 2018 ; Savić & Schwank, 2016 ; Zhao et al, 2019 ). In 2014, CRISPR/Cas9 technology was successfully used to create the first genome-edited rabbit model ( Figure 1 ) ( Yang et al, 2014 ), with more than 50 genome-edited rabbit models developed since ( Xu et al, 2021b ).…”

Section: Novel Genome-editing Approaches For Rabbit Modelingmentioning

confidence: 99%

“…Given the above species-specific advantages, genome-edited rabbits are superior models for mimicking the pathogenic characteristics of diverse human genetic diseases. In recent years, researchers have successfully established genome-edited rabbit models for a growing number of human diseases, including cardiovascular diseases (CVD), immune system-related diseases, ocular diseases, and neurological disorders ( Table 3 ) ( Fan et al, 2021 ; Song et al, 2020a ; Xu et al, 2021b ; Zhang et al, 2022b ), leading to an improved understanding of disease pathophysiology and ability to develop therapeutic interventions ( Figure 2 ).…”

Section: Generation Of Genome-edited Rabbits In Biomedical Researchmentioning

confidence: 99%

Genome-edited rabbits: Unleashing the potential of a promising experimental animal model across diverse diseases

Han,

Zhou,

Zhang

et al. 2024

Zoological Research

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Animal models are extensively used in all aspects of biomedical research, with substantial contributions to our understanding of diseases, the development of pharmaceuticals, and the exploration of gene functions. The field of genome modification in rabbits has progressed slowly. However, recent advancements, particularly in CRISPR/Cas9-related technologies, have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases, including cardiovascular disorders, immunodeficiencies, aging-related ailments, neurological diseases, and ophthalmic pathologies. These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice. This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine, underscoring their impact and future potential in translational medicine.

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Gene Editing in Rabbits: Unique Opportunities for Translational Biomedical Research

Cited by 10 publications

References 120 publications

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

The High-Level Expression Analysis of RhPA In The RhPA/gGH Double-Transgenic Rabbits And Its Thrombolysis Activity In Vitro

Genome-edited rabbits: Unleashing the potential of a promising experimental animal model across diverse diseases

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