Cytosine base editors (CBEs) and adenine base editors (ABEs) are recently developed CRISPR-mediated genome-editing tools that do not introduce double-strand breaks. In this study, five ABEs, ABE7.10, ABEmax, NG-ABEmax, ABE8e and NG-ABE8e, were used to generate A-to-G (T-to-C) conversions in five genome loci in porcine fetal fibroblasts (PFFs). Variable yet appreciable editing efficiencies and variable activity windows were observed in these targeting regions via these five editors. The strategy of two sgRNAs in one vector exhibited superior editing efficiency to that of using two separate sgRNA expression vectors. ABE-mediated start-codon mutation in APOE silenced its expression of protein and, unexpectedly, eliminated the vast majority of its mRNA. No off-target DNA site was detected for these editors. Substantial off-target RNA events were present in the ABE-edited cells, but no KEGG pathway was found to be significantly enriched. Our study supports that ABEs are powerful tools for A-to-G (T-to-C) point-mutation modification in porcine cells.

03 Jan 2023·Journal of Animal Science

Pulmonary microbiota intervention alleviates fine particulate matter-induced lung inflammation in broilers

Article

Author: Li, Chunmei ; Shen, Dan ; Win-Shwe, Tin-Tin ; Nagaoka, Kentaro ; Zhou, Zilin ; Li, Mingyang ; Wang, Kai ; Liu, Junze

AbstractFine particulate matter (PM2.5) released during the livestock industry endangers the respiratory health of animals. Our previous findings suggested that broilers exposed to PM2.5 exhibited lung inflammation and changes in the pulmonary microbiome. Therefore, this study was to investigate whether the pulmonary microbiota plays a causal role in the pathogenesis of PM2.5-induced lung inflammation. We first used antibiotics to establish a pulmonary microbiota intervention broiler model, which showed a significantly reduced total bacterial load in the lungs without affecting the microbiota composition or structure. Based on it, 45 AA broilers of similar body weight were randomly assigned to three groups: control (CON), PM2.5 (PM), and pulmonary microbiota intervention (ABX-PM). From 21 d of age, broilers in the ABX-PM group were intratracheally instilled with antibiotics once a day for 3 d. Meanwhile, broilers in the other two groups were simultaneously instilled with sterile saline. On 24 and 26 d of age, broilers in the PM and ABX-PM groups were intratracheally instilled with PM2.5 suspension to induce lung inflammation, and broilers in the CON group were simultaneously instilled with sterile saline. The lung histomorphology, inflammatory cytokines’ expression levels, lung microbiome, and microbial growth conditions were analyzed to determine the effect of the pulmonary microbiota on PM2.5-induced lung inflammation. Broilers in the PM group showed lung histological injury, while broilers in the ABX-PM group had normal lung histomorphology. Furthermore, microbiota intervention significantly reduced mRNA expression levels of interleukin-1β, tumor necrosis factor-α, interleukin-6, interleukin-8, toll-like receptor 4 and nuclear factor kappa-B. PM2.5 induced significant changes in the β diversity and structure of the pulmonary microbiota in the PM group. However, no significant changes in microbiota structure were observed in the ABX-PM group. Moreover, the relative abundance of Enterococcus cecorum in the PM group was significantly higher than that in the CON and ABX-PM groups. And sterile bronchoalveolar lavage fluid from the PM group significantly promoted the growth of E. cecorum, indicating that PM2.5 altered the microbiota’s growth condition. In conclusion, pulmonary microbiota can affect PM2.5-induced lung inflammation in broilers. PM2.5 can alter the bacterial growth environment and promote dysbiosis, potentially exacerbating inflammation.

09 May 2022·BiomacromoleculesQ2 · CHEMISTRY

Poly(beta-amino ester)-Based Nanoparticles Enable Nonviral Delivery of Base Editors for Targeted Tumor Gene Editing

Q2 · CHEMISTRY

Article

Author: Li, Jinwei ; Cao, Yan ; Qin, Jianchao ; Li, Jianfeng ; Chen, Qimingxing ; Wu, Qingxia ; He, Zongxing ; Huang, Xingxu ; Su, Lili ; He, Xiaoyan ; Yang, Huiying

Base editing is an emerging genome editing technology with the advantages of precise base corrections, no double-strand DNA breaks, and no need for templates, which provides an alternative treatment option for tumors with point mutations. However, effective nonviral delivery systems for base editors (BEs) are still limited. Herein, a series of poly(beta-amino esters) (PBAEs) with varying backbones, side chains, and end caps were synthesized to deliver plasmids of BEs and sgRNA. Efficient transfection and base editing were achieved in HEK-293T-sEGFP and U87-MG-sEGFP reporter cell lines by using lead PBAEs, which were superior to PEI and lipo3k. A single intratumor injection of PBAE/pDNA nanoparticles induced the robust conversion of stopped-EGFP into EGFP in mice bearing xenograft glioma tumors, indicating successful gene editing by ABEmax-NG. Overall, these results demonstrated that PBAEs can efficiently deliver BEs for tumor gene editing both in vitro and in vivo.

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Indication	Highest Phase	Country/Location	Organization	Date
Central Nervous System Diseases	Preclinical	US	Autobahn Therapeutics, Inc.Startup	-

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