Low-dose AAV-CRISPR-mediated liver-specific knock-in restored hemostasis in neonatal hemophilia B mice with subtle antibody response

Xiangjun He, Zhenjie Zhang, Junyi Xue, Yaofeng Wang, Siqi Zhang, Junkang Wei, Chenzi Zhang, Jue Wang, Brian Anugerah Urip, Chun Christopher Ngan, Junjiang Sun, Yuefeng Li, Zhiqian Lu, Hui Zhao, Duanqing Pei, Chi-Kong Li and Bo Feng ()
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Xiangjun He: The Chinese University of Hong Kong
Zhenjie Zhang: The Chinese University of Hong Kong
Junyi Xue: The Chinese University of Hong Kong
Yaofeng Wang: Chinese Academy of Sciences
Siqi Zhang: The Chinese University of Hong Kong
Junkang Wei: The Chinese University of Hong Kong
Chenzi Zhang: The Chinese University of Hong Kong
Jue Wang: The Chinese University of Hong Kong
Brian Anugerah Urip: The Chinese University of Hong Kong
Chun Christopher Ngan: The Chinese University of Hong Kong
Junjiang Sun: University of North Carolina
Yuefeng Li: Guangdong Landau Biotechnology Co.Ltd
Zhiqian Lu: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Hui Zhao: The Chinese University of Hong Kong
Duanqing Pei: Chinese Academy of Sciences
Chi-Kong Li: The Chinese University of Hong Kong
Bo Feng: The Chinese University of Hong Kong

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract AAV-delivered CRISPR/Cas9 (AAV-CRISPR) has shown promising potentials in preclinical models to efficiently insert therapeutic gene sequences in somatic tissues. However, the AAV input doses required were prohibitively high and posed serious risk of toxicity. Here, we performed AAV-CRISPR mediated homology-independent knock-in at a new target site in mAlb 3’UTR and demonstrated that single dose of AAVs enabled long-term integration and expression of hF9 transgene in both adult and neonatal hemophilia B mice (mF9 −/−), yielding high levels of circulating human Factor IX (hFIX) and stable hemostasis restoration during entire 48-week observation period. Furthermore, we achieved hemostasis correction with a significantly lower AAV dose (2 × 109 vg/neonate and 1 × 1010 vg/adult mouse) through liver-specific gene knock-in using hyperactive hF9R338L variant. The plasma antibodies against Cas9 and AAV in the neonatal mice receiving low-dose AAV-CRISPR were negligible, which lent support to the development of AAV-CRISPR mediated somatic knock-in for treating inherited diseases.

Date: 2022
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DOI: 10.1038/s41467-022-34898-y

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