Therapeutically relevant engraftment of a CRISPR-Cas9-edited HSC-enriched population with HbF reactivation in nonhuman primates.
Therapeutically relevant engraftment of a CRISPR-Cas9-edited HSC-enriched population with HbF reactivation in nonhuman primates.
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DOI：
10.1126/scitranslmed.aaw3768
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发表时间：
2019-07-31
影响因子：
17.1
通讯作者：
Kiem HP
中科院分区：
文献类型：
--
作者：
Humbert O;Radtke S;Samuelson C;Carrillo RR;Perez AM;Reddy SS;Lux C;Pattabhi S;Schefter LE;Negre O;Lee CM;Bao G;Adair JE;Peterson CW;Rawlings DJ;Scharenberg AM;Kiem HP
胎儿血红蛋白（HbF）的重新激活正在寻求作为血红蛋白病的治疗策略。在这里，我们评估了用CRISPR/Cas9核酸酶平台编辑的造血干细胞和祖细胞（HSPC）的治疗潜力，以重现在表达增加量的HbF的个体中鉴定的天然突变，这种情况称为HbF的遗传持久性。CRISPR/Cas9处理和在非人灵长类动物（NHP）自体移植模型中基于CD 34受体的表面表达纯化的HSPC的移植导致高达30%的基因编辑的细胞植入>1年。经编辑的细胞有效且稳定地再活化HbF，如外周血中高达18%的表达HbF的红细胞所证明的。通过编辑高度富集的干细胞（由标记物CD 34 + CD 90 + CD 45 RA-定义）获得了类似的结果，允许移植的靶细胞数量减少10倍，从而避免了与规模扩大相关的问题，并大大减少了对编辑试剂的需求。使用这种方法移植的基因编辑细胞在体内持续存在的频率可能足以改善许多遗传疾病的表型。CRISPR/Cas9编辑的造血干细胞在非人灵长类动物中产生长期植入和胎儿血红蛋白再活化。
Reactivation of fetal hemoglobin (HbF) is being pursued as a treatment strategy for hemoglobinopathies. Here, we evaluated the therapeutic potential of hematopoietic stem and progenitor cells (HSPCs) edited with the CRISPR/Cas9 nuclease platform to recapitulate naturally occurring mutations identified in individuals who express increased amounts of HbF, a condition known as hereditary persistence of HbF. CRISPR/Cas9 treatment and transplantation of HSPCs purified on the basis of surface expression of the CD34 receptor in a nonhuman primate (NHP) autologous transplantation model resulted in up to 30% engraftment of gene-edited cells for >1 year. Edited cells effectively and stably reactivated HbF, as evidenced by up to 18% HbF-expressing erythrocytes in peripheral blood. Similar results were obtained by editing highly enriched stem cells, defined by the markers CD34+CD90+CD45RA–, allowing for a 10-fold reduction in the number of transplanted target cells, thus circumventing issues associated with scale-up and considerably reducing the need for editing reagents. The frequency of engrafted, gene-edited cells persisting in vivo using this approach may be sufficient to ameliorate the phenotype for a number of genetic diseases. CRISPR/Cas9-edited hematopoietic stem cells produce long-term engraftment and fetal hemoglobin reactivation in nonhuman primates.
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CD33在造血干细胞中的遗传失活，使CAR T细胞免疫疗法患有急性髓样白血病。
影响因子：
64.5
作者：
Kim MY;Yu KR;Kenderian SS;Ruella M;Chen S;Shin TH;Aljanahi AA;Schreeder D;Klichinsky M;Shestova O;Kozlowski MS;Cummins KD;Shan X;Shestov M;Bagg A;Morrissette JJD;Sekhri P;Lazzarotto CR;Calvo KR;Kuhns DB;Donahue RE;Behbehani GK;Tsai SQ;Dunbar CE;Gill S
通讯作者：
Gill S
影响因子：
14.8
作者：
Bak RO;Dever DP;Porteus MH
通讯作者：
Porteus MH
影响因子：
16.6
作者：
Adair, Jennifer E.;Waters, Timothy;Kiem, Hans-Peter
通讯作者：
Kiem, Hans-Peter
DOI：
10.1111/j.1749-6632.1998.tb10460.x
发表时间：
1998-01-01
期刊：
COOLEYS ANEMIA
影响因子：
--
作者：
Forget, BG
通讯作者：
Forget, BG
DOI：
10.1016/j.omtm.2018.12.008
发表时间：
2019-03-15
影响因子：
4.7
作者：
Lux, Christopher T.;Pattabhi, Sowmya;Rawlings, David J.
通讯作者：
Rawlings, David J.