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000169364 1001_ $$aAlJanahi, Aisha A$$b0
000169364 245__ $$aPrediction and Validation of Hematopoietic Stem and Progenitor Cell Off-Target Editing in Transplanted Rhesus Macaques.
000169364 260__ $$aNew York, NY$$bNature Publ. Group$$c2022
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000169364 500__ $$a2022 Jan 5;30(1):209-222
000169364 520__ $$aThe programmable nuclease technology CRISPR/Cas9 has revolutionized gene editing in the last decade. Due to the risk of off-target editing, accurate and sensitive methods for off-target characterization are crucial prior to applying CRISPR/Cas9 therapeutically. Here, we utilized a rhesus macaque model to compare the predictive values of CIRCLE-seq, an in vitro off-target prediction method, with in silico prediction (ISP) based solely on genomic sequence comparisons. We use AmpliSeq HD error-corrected sequencing to validate off-target sites predicted by CIRCLE-seq and ISP for a CD33 gRNA with thousands of off-target sites predicted by ISP and CIRCLE-seq. We found poor correlation between the sites predicted by the two methods. When almost 500 sites predicted by each method were analyzed by error-corrected sequencing of hematopoietic cells following transplantation, 19 off-target sites revealed insertion/deletion mutations. Of these sites, 8 were predicted by both methods, 8 by CIRCLE-seq only, and 3 by ISP only. The levels of cells with these off-target edits exhibited no expansion or abnormal behavior in vivo in animals followed for up to 2 years. In addition, we utilized an unbiased method termed CAST-Seq to search for translocations between the on-target site and off-target sites present in animals following transplantation, detecting one specific translocation that persisted in blood cells for at least one year following transplantation. In conclusion, neither CIRCLE-seq or ISP predicted all sites, and a combination of careful gRNA design, followed by screening for predicted off-target sites in target cells by multiple methods may be required for optimizing safety of clinical development.
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000169364 7001_ $$aLazzarotto, Cicera R$$b1
000169364 7001_ $$aChen, Shirley$$b2
000169364 7001_ $$aShin, Tae-Hoon$$b3
000169364 7001_ $$aCordes, Stefan$$b4
000169364 7001_ $$aFan, Xing$$b5
000169364 7001_ $$aJabara, Isabel$$b6
000169364 7001_ $$aZhou, Yifan$$b7
000169364 7001_ $$aYoung, David J$$b8
000169364 7001_ $$aLee, Byung-Chul$$b9
000169364 7001_ $$aYu, Kyung-Rok$$b10
000169364 7001_ $$aLi, Yuesheng$$b11
000169364 7001_ $$aToms, Bradley$$b12
000169364 7001_ $$aTunc, Ilker$$b13
000169364 7001_ $$aHong, So Gun$$b14
000169364 7001_ $$aTruitt, Lauren L$$b15
000169364 7001_ $$aKlermund, Julia$$b16
000169364 7001_ $$0P:(DE-He78)a355989a6a384c85ecb759b528e07796$$aAndrieux, Geoffroy$$b17$$udkfz
000169364 7001_ $$aKim, Miriam Y$$b18
000169364 7001_ $$aCathomen, Toni$$b19
000169364 7001_ $$aGill, Saar$$b20
000169364 7001_ $$aTsai, Shengdar Q$$b21
000169364 7001_ $$aDunbar, Cynthia E$$b22
000169364 773__ $$0PERI:(DE-600)2001818-6$$a10.1016/j.ymthe.2021.06.016$$gp. S1525001621003221$$n1$$p209-222$$tMolecular therapy$$v30$$x1525-0016$$y2022
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