美国哈佛医学院David A. Williams团队研究了BCL11A转录后基因沉默治疗镰状细胞病的疗效。2020年12月5日，该研究发表在《新英格兰医学杂志》上。

镰状细胞病的特征是溶血性贫血、疼痛和进行性器官损伤。高水平的由α-和γ-珠蛋白组成的红细胞-胎儿血红蛋白（HbF）可通过减轻镰状血红蛋白聚合和红细胞镰状化来改善这些症状。BCL11A是成人红细胞中γ珠蛋白表达和HbF产生的抑制因子，它的下调是诱导HbF的有潜力的治疗策略。

研究组进行了一项单中心、开放标签的先导研究，纳入镰状细胞病患者。研究治疗包括输注自体CD34+细胞和BCH-BB694慢病毒载体，慢病毒载体编码一个短发夹状RNA（shRNA），靶向嵌在microRNA（shmiR） 中的BCL11A mRNA，允许红系特异性敲除。研究组对患者的主要移植终点和安全性，以及治疗的血液学和临床缓解率进行了评估。

截至2020年10月，研究组对接受BCH-BB694基因治疗后的6例患者进行了至少6个月的随访，中位随访时间为18个月。所有患者均已移植，且不良反应与预备化疗一致。所有可充分评估的患者都达到了强而稳定的HbF诱导，HbF广泛分布在红细胞中，每个F-细胞的HbF为9.0-18.6 pg /细胞。在随访期间，镰状细胞病的临床表现减少或消失。

总之，该研究证实了BCL11A抑制是HbF诱导的有效靶点，并初步证明基于shmiR的基因敲除在镰状细胞病中具有较好的临床获益。

附：英文原文

Title: Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease

Author: Erica B. Esrick, M.D.,, Leslie E. Lehmann, M.D.,, Alessandra Biffi, M.D., Ph.D.,, Maureen Achebe, M.D.,, Christian Brendel, Ph.D.,, Marioara F. Ciuculescu, M.D.,, Heather Daley, B.S.,, Brenda MacKinnon, B.S.N., R.N.,, Emily Morris, M.P.H.,, Amy Federico, C.P.N.P.,, Daniela Abriss, Ph.D.,, Kari Boardman, B.S.,, Radia Khelladi, B.S.,, Kit Shaw, Ph.D.,, Helene Negre, Ph.D.,, Olivier Negre, Ph.D.,, Sarah Nikiforow, M.D., Ph.D.,, Jerome Ritz, M.D.,, Sung-Yun Pai, M.D.,, Wendy B. London, Ph.D.,, Colleen Dansereau, M.S.N., R.N., C.P.N.,, Matthew M. Heeney, M.D.,, Myriam Armant, Ph.D.,, John P Manis, M.D.,, and David A. Williams, M.D.

Issue&Volume: 2020-12-05

Abstract:

Background

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.

Methods

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.

Results

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 41.5%), 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.

Conclusions

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.

DOI: 10.1056/NEJMoa2029392

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2029392