Production of CFTR-ΔF508 Rabbits

Yang, Dongshan; Pallas, Brooke; Hoenerhoff, Mark J.; Ren, Zhuoying; Han, Renzhi; Zhang, Jifeng; Chen, Y. Eugene; Jin, Jian‐Ping; Sun, Fei; Xu, Jie

doi:10.3389/fgene.2020.627666

Cited by 10 publications

(8 citation statements)

References 29 publications

(34 reference statements)

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“…First, the CF-9 mutation is an artificial mutation created by CRISPR/Cas9, which is not reported in CF patients. Although, we predict this mutation is similar to that of F508del, it is important to evaluate and confirm the findings in our newly developed F508del rabbits ( 65 ). Second, the disease phenotypes are relatively consistent in the cohort of animals (e.g., more than half showed NASH-like phenotypes), which differs from the huge variation of disease manifestation of CFLD in human patients.…”

Section: Discussionmentioning

confidence: 63%

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: 63%

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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“…Secondly, the present work uses CF rabbits with a mutation (i.e., CF-9) that is not present in CF patients. To further confirm our observations, it is necessary to evaluate sotagliflozin in the recently developed CFTR-F508del rabbits ( 12 ) and in other CF animals carrying clinically relevant mutations. Thirdly, in the present work, we did not treat the CF rabbits with Trikafta.…”

Section: Discussionmentioning

confidence: 73%

“…We measured the SGLT1 expression by Western blotting, quantitative real-time PCR (RT-qPCR), and immunohistochemistry (IHC) staining analyses in the lung, pancreas, intestine, and liver in CF rabbits. We discovered that SGLT1 was universally upregulated in all these tissues in the CF-9 rabbits ( Figure 1, A–C ), as well as in those of CF rabbits carrying different CFTR mutations, which include a CF-1 line that mimics a class I null mutation ( 11 ) and the recently developed CFTR-F508del line ( 12 ) that represents the most dominant patient mutation ( Supplemental Figure 1 , A and B; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.165826DS1 ). In contrast, while the SGLT2 expression was highly abundant in the kidney tissue, as expected, it was very low in the CF-affected organs ( Supplemental Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

Sotagliflozin attenuates liver associated disorders in cystic fibrosis rabbits

Liang,

Hou,

Bouhamdan

et al. 2024

JCI Insight

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Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene lead to CF, a life-threating autosomal recessive genetic disease. While recently approved Trikafta dramatically ameliorates CF lung diseases, there is still a lack of effective medicine to treat CF-associated liver disease (CFLD). To address this medical need, we used a recently established CF rabbit model to test whether sotagliflozin, a sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor drug that is approved to treat diabetes, can be repurposed to treat CFLD. Sotagliflozin treatment led to systemic benefits to CF rabbits, evidenced by increased appetite and weight gain as well as prolonged lifespan. For CF liver-related phenotypes, the animals benefited from normalized blood chemistry and bile acid parameters. Furthermore, sotagliflozin alleviated nonalcoholic steatohepatitis–like phenotypes, including liver fibrosis. Intriguingly, sotagliflozin treatment markedly reduced the otherwise elevated endoplasmic reticulum stress responses in the liver and other affected organs of CF rabbits. In summary, our work demonstrates that sotagliflozin attenuates liver disorders in CF rabbits and suggests sotagliflozin as a potential drug to treat CFLD.

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“…Prime editor was successfully used in generating a Tay-Sachs disease (TSD) rabbit model in 2021 [Table 2], which is a model of neurological disease generated by prime editor-mediated four base insertion [98] . ZFN APOE KO Lipid metabolism and atherosclerosis [50] ZFN CETP KO Lipid metabolism and atherosclerosis [51] TALENs RAG1; RAG2 KO Immunodeficiency [52] TALENs FAH KO Hereditary tyrosinemia type 1 [53] CRISPR/Cas9 FBN1 KO Marfanoid progeroid lipodystrophy syndrome [54] CRISPR/Cas9 DMD KO Duchenne muscular dystrophy [55] CRISPR/Cas9 ANO5 KO Muscular dystrophy [56] CRISPR/Cas9 α-Crystallin KO Congenital cataracts [57] CRISPR/Cas9 GJA8 KO Congenital cataracts [58] CRISPR/Cas9 LDLR KO Lipid metabolism and atherosclerosis [59] CRISPR/Cas9 MSTN KO Muscle hypertrophy [60,61] CRISPR/Cas9 SRY KO Sex reversal syndromes and hermaphroditism syndromes [53,54] CRISPR/Cas9 PHEX KO X-linked hypophosphatemia [62] CRISPR/Cas9 LMNA KO Premature aging syndrome [63] CRISPR/Cpf1 WRN KO Werner syndrome [64] CRISPR/Cas9 TYR KO Oculocutaneous albinism [65,66] CRISPR/Cas9 DMP1 KO Mineralization defects [67] CRISPR/Cas9 GADD45G KO Congenital cleft palate [68] CRISPR/Cas9 HOXC13 KO Hair and nail ectodermal dysplasia [69] CRISPR/Cas9 GCK KO Maturity-onset diabetes of the young type 2 [70] CRISPR/Cas9 HBB2 KO β-thalassemia [71] CRISPR/Cas9 WAS KO Wiskott-Aldrich syndrome [72] CRISPR/Cas9 CBS KO Congenital hyper-homocysteinemia [73] CRISPR/Cas9 LDLR; APOE KO Lipid metabolism and atherosclerosis [74] CRISPR/Cas9 APOC3 KO Lipid metabolism and atherosclerosis [75] CRISPR/Cas9 CFTR KO Cystic fibrosis [76] CRISPR/Cas9 CFTR KO ΔF508 Cystic fibrosis [77] CRISPR/Cas9 CLPG KO Muscular hypertrophy syndrome [69] CRISPR/Cas9 FGF5 KO Long hair…”

Section: Production Of Genome-modified Rabbit Disease Models Via Cris...mentioning

confidence: 99%

Genome-edited rabbit, a prospective alternative model for neurological diseases

Zhang¹,

Song²,

Lai³

et al. 2022

Ageing Neur Dis

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Animal models have great importance in the research of human neurodegenerative diseases due to their value in symptom mimicking, mechanism investigation, and preclinical tests. Although non-human primate and large animal models have good performance in disease modeling due to their high maintenance cost and critical ethical standards, rodent models are commonly used. Rodent models have been successfully applied in modeling many neurological diseases; however, their genetic background, neuroanatomical features, and nervous system development are different from those of humans. Moreover, the short lifespan and small body size of rodent models also limit the monitoring of disease progression and observation of clinical symptoms in studying neuronal disorders that are late-onset or have a long course of progression. In comparison with rodents, rabbits are phylogenetically closer to humans and have closer similarities to humans in brain development, thus are an alternate animal model for human neurological diseases.

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Production of CFTR-ΔF508 Rabbits

Cited by 10 publications

References 29 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

Sotagliflozin attenuates liver associated disorders in cystic fibrosis rabbits

Genome-edited rabbit, a prospective alternative model for neurological diseases

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