Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.
Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.
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DOI：
10.1056/nejmoa2029392
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发表时间：
2021-01-21
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影响因子：
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通讯作者：
Williams DA
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作者：
Esrick EB;Lehmann LE;Biffi A;Achebe M;Brendel C;Ciuculescu MF;Daley H;MacKinnon B;Morris E;Federico A;Abriss D;Boardman K;Khelladi R;Shaw K;Negre H;Negre O;Nikiforow S;Ritz J;Pai SY;London WB;Dansereau C;Heeney MM;Armant M;Manis JP;Williams DA
镰状细胞病的特征是溶血性贫血、疼痛和进行性器官损害。高水平的红细胞胎儿血红蛋白(HbF)包括α-和γ-珠蛋白，可能通过减轻镰状血红蛋白聚合和红细胞病态来改善这些表现。BCL11A是成人红细胞γ-珠蛋白表达和HbF产生的抑制因子。它的下调是一种很有前景的诱导HBF的治疗策略。我们招募了镰状细胞病患者参加一项单中心、开放标签的先导性研究。研究治疗包括输注BCH-BB694慢病毒载体转导的自体CD34+细胞，该载体编码针对嵌入在microRNA(ShmiR)中的BCL11A mRNA的短发夹状RNA(ShRNA)，允许红系特异性敲除。评估患者植入的主要终点和安全性，以及血液学和临床对治疗的反应。截至2020年10月，6名患者在接受BCH-BB694基因治疗后至少随访6个月；中位随访时间为18个月(范围为7至29个月)。所有患者均有植入，不良反应与预备性化疗的效果一致。所有能得到充分评价的患者均获得了稳健稳定的HBF诱导(最近一次随访的HBF/(F+S)百分比为20.4%~41.3%)，HBF广泛分布于红细胞(F细胞占未输血红细胞的58.9%~93.6%)，每个F细胞的HBF为9.0~18.6pg/细胞。随访期内镰状细胞病的临床表现减少或消失。这项研究证实了抑制BCL11A是诱导HBF的有效靶点，并提供了初步证据，表明基于shmiR的基因敲除在镰状细胞疾病中提供了有利的风险-益处分布。(由美国国立卫生研究院资助；ClinicalTrials.gov编号，NCT03282656)
Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR), allowing erythroid lineage–specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment. As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk–benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656)