CRISPR-Cas9: A method for establishing rat models of drug metabolism and pharmacokinetics

Lu, Jian; Liu, Jie; Guo, Yuanqing; Zhang, Yuanjin; Xu, Yeye; Wang, Xin

doi:10.1016/j.apsb.2021.01.007

Cited by 25 publications

(14 citation statements)

References 71 publications

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“…In 2020, the Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer A. Doudna for their great contributions to the CRISPR/Cas9 technology. The construction of gene editing rats by CRISPR/Cas9 technology has made great progress in drug metabolism and pharmacokinetics (Lu et al, 2021). For example, we have successfully constructed CYP2E1 (-/-) (Wang et al, 2016), CYP3A1/2 (-/-) (Lu et al, 2017), CYP2J3/10 (-/-) (Lu et al, 2020a), Mdr1a/b (-/-) (Liang et al, 2019), and Slco1b2 (-/-) (Ma et al, 2020) rat models through CRISPR/Cas9, and applied them to the exploration of pharmacokinetics and drug-drug interactions Qin et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Sun

Zhang

et al. 2021

Drug Metab Dispos

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Cytochrome P450 1A2 (CYP1A2) as one of the most important CYP isoforms is involved in the biotransformation of many important endogenous and exogenous substances. CYP1A2 also plays an important role in the development of many diseases because it is involved in the biotransformation of precancerous substances and poisons. Although the generation of Cyp1a2 knockout (KO) mouse model has been reported, there are still no relevant rat models for the study of CYP1A2-mediated pharmacokinetics and diseases. In this report, CYP1A2 KO rat model was established successfully by CRISPR/Cas9 without any detectable off-target effect. Compared with wild-type rats, this model showed a loss of CYP1A2 protein expression in the liver. The results of pharmacokinetics in vivo and incubation in vitro of specific substrates of CYP1A2 confirmed the lack of function of CYP1A2 in KO rats. In further studies of potential compensatory effects, we found that CYP1A1 was significantly up-regulated, and CYP2E1, CYP3A2 and LXRβ were down-regulated in KO rats. In addition, CYP1A2 KO rats exhibited a significant increase in serum cholesterol and free testosterone, accompanied by mild liver damage and lipid deposition, suggesting that CYP1A2 deficiency affects lipid metabolism and liver function to a certain extent. In summary, we successfully constructed the CYP1A2 KO rat model, which provides a useful tool for studying the metabolic function and physiological function of CYP1A2.

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Section: Introductionmentioning

confidence: 99%

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Sun

Zhang

et al. 2021

Drug Metab Dispos

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“…CRISPR-Cas is an adaptive immune system found in bacteria and archaea. This technology is a third-generation artificial nuclease technology based on the CRISPR-Cas system and is believed to be a powerful gene-editing tool [35].…”

Section: Genome Editing Technology As a Methods For Deleting Rnls In Cell Bmentioning

confidence: 99%

Deletion of the RNLS Gene using CRISPR/Cas9 as Pancreatic Cell β Protection against Autoimmune and ER Stress for Type 1 Diabetes Mellitus

Baraja

Sunarto

Adji

et al. 2021

Open Access Maced J Med Sci

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BACKGROUND: Type 1 diabetes mellitus (T1DM) is a chronic disease in children which is usually caused by autoimmunity that damages pancreatic a and b cells which have functions as blood glucose regulators. Some studies stated that Renalase (RNLS) gene deletion will protect these b cells from autoimmune reactions and Endoplasmic Reticulum (ER) stress. RNLS deletion by genome editing Clustered Regular interspersed Short Palindromic Repeats-CRISPR-related (CRISPR/Cas9) is believed to have the potential to be a therapy for T1DM Patients. AIM: This research was conducted to know the potential of RNLS deletion using the CRISPR/Cas9 as an effective therapy and whether it has a permanent effect on T1DM patients. METHODS: The method applied in this research summarized articles by analyzing the titles and abstracts of various predetermined keywords. In this case, the author chose a full-text article published within the past 10 years by prioritizing searches in the last 5 years through PubMed, Google Scholar, Science Direct, Cochrane, American Diabetes Association, and official guidelines from IDAI. RESULTS: RNLS deletion using CRISPR/Cas9 in mice weakened the response of polyclonal -cell-reactive CD8+ T cells and disrupted the immune recognition to cells so that autoimmune killing did occur. In addition, such deletion prevents RNLS ER stress by increasing the threshold, triggering the unfolded protein response so that ER stress is difficult to occur. RNLS mutations in b cells also increase b cell survivability to oxidative stress. CONCLUSION: b cells RNLS deletion by genome editing CRISPR/Cas9 is effective in protecting b cells from autoimmune reactions and RE stress. However, further research is needed to determine the side effects and safety of its use.

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“…A Bsep knockout model, in which the Abcb11 gene is knocked out by ZFN technology in Sprague–Dawley rats, has become a useful tool to study bile acid disposition and compensatory gene regulation 160 . Recently, the powerful gene editing technology of clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) has been increasingly applied for studying ADME gene function in cell lines or in animals 161 , 162 , as exemplified by the Cyp2d knock-out/human CYP2D6 knock-in 163 , and Slco1b2 gene knockout rats 164 . The MDCK cell line with canine Abcb1 gene knockout is a valuable tool for permeability assessment and is routinely used in major pharmaceutical companies 165 .…”

Section: Major Advances In Human Clearance Prediction For Small-molec...mentioning

confidence: 99%

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Lai¹,

Chu²,

Di³

et al. 2022

Acta Pharmaceutica Sinica B

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CRISPR-Cas9: A method for establishing rat models of drug metabolism and pharmacokinetics

Cited by 25 publications

References 71 publications

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Deletion of the RNLS Gene using CRISPR/Cas9 as Pancreatic Cell β Protection against Autoimmune and ER Stress for Type 1 Diabetes Mellitus

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

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