CRISPR_SCD001的研发：CRISPR-Cas9介导校正后的自体造血干细胞基因治疗镰状细胞病
Development of CRISPR_SCD001, an Autologous Hematopoietic Stem Cell Gene Therapy for Sickle Cell Disease after CRISPR-Cas9 Mediated Correction
镰状细胞病的根源是HBB基因的镰状突变，本研究开发了自体细胞疗法CRISPR_SCD001，用CRISPR-Cas9介导的同源定向修复，配合单链寡脱氧核苷酸作为修复模板来校正该突变。研究用镰状患者和健康供者动员后的外周血CD34阳性细胞制备产品，考察疗效潜力、遗传毒性和小鼠体内安全性。大规模制备的产品纯度约89%，平均基因校正率约22%，校正后的红细胞培养物产生约39%成人血红蛋白和40%胎儿血红蛋白，镰状血红蛋白从89%降至约22%。在人源化小鼠中植入良好、编辑比例稳定、克隆分布多克隆，未见明显治疗相关毒性。该数据支持启动针对重症镰状患者的首次人体1期试验。
为什么推荐给您：自体基因校正产品完成系统临床前验证并准备首次人体试验，属值得关注的转化进展。
不需要生物学背景，多打比方
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摘要Abstract
We developed CRISPR_SCD001, an autologous cellular therapy in which the pathogenic HBB sickle allele is corrected by CRISPR-Cas9-mediated homology-directed repair using a single-stranded oligodeoxyribonucleotide as DNA donor template. The Drug Product (DP) from Plerixafor-mobilized peripheral-blood CD34+ cells from sickle and healthy donors were used for: 1) pharmacodynamic assessments to interrogate therapeutic potential; 2) evaluation of genotoxicity; and 3) in vivo characterization by a non-GLP toxicology study in NBSGW mice. Large-scale DP lots yielded 89 ± 5 % CD34+ purity with 84 ± 6 % viability. Mean gene correction at HBB was 22 ± 4 % of alleles, with 51 ± 6 % of allelic disruption. Edited erythroid cultures produced 39 ± 5 % adult hemoglobin and 40 ± 6 % fetal hemoglobin, reducing sickle hemoglobin from 89% to 22 ± 6 %. In NBSGW mice, CRISPR_SCD001 engrafted robustly (59 ± 25%), maintained editing frequencies comparable to injected cells (∼20% gene correction), showed polyclonal distribution of the edited cells, and no noteworthy treatment-related toxicity or pathologic evident were found by a blinded histopathology assessment. Our protocol generates a clinical-grade, cryopreserved CD34+ cell product that corrects the sickle mutation, restores anti-sickling hemoglobins, and meets pre-clinical safety criteria, establishing a reproducible manufacturing process suitable for clinical translation. These data support initiation of a first-in-human phase I trial of CRISPR_SCD001 for sickle patients presenting with severe pathology.