Gene therapy targeting BCL11A to induce fetal hemoglobin and reduce sickle hemoglobin in patients with Sickle Cell Disease

靶向 BCL11A 的基因疗法可诱导胎儿血红蛋白并降低镰状细胞病患者的镰状血红蛋白

• 批准号: 9363943
• 负责人: DAVID A WILLIAMS
• 金额: $ 167.34万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9363943
• 关键词: Adult; Allogenic; Architecture; Attenuated; Autologous; Biological; Blood; Cells; Clinical; Clinical Trials; Data; Disease; Engraftment; Erythrocytes; Erythroid; Erythroid Cells; Feasibility Studies; Fetal Hemoglobin; Fetal Reduction; Future; Gene Expression; Gene Transfer; Gene-Modified; Genes; Half-Life; Health; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobin; Hemoglobinopathies; Human; Incidence; Individual; Laboratories; Lead; Life; MicroRNAs; Molecular; Outcome; Patients; Phenotype; Protocols documentation; Publishing; Risk; Series; Severities; Siblings; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Stem cells; Toxic effect; Transgenes; Transplantation; Virus; base; beta Thalassemia; chronic graft versus host disease; clinical effect; cohort; curative treatments; cytotoxicity; disease phenotype; fetal; gamma Globin; gene therapy; gene transfer vector; graft failure; graft vs host disease; improved; in vivo; knock-down; mathematical model; mortality; mouse model; mutant; phase I trial; polymerization; pre-clinical; prevent; safety and feasibility; sickling; small hairpin RNA; targeted treatment; vector

Induction of fetal hemoglobin (HbF) in both sickle cell disease (SCD) and β-thalassemia is an extremely promising approach to ameliorate the severity of both diseases. Recent molecular studies have revealed new regulators of the fetal-to-adult hemoglobin switch in humans, including BCL11A. BCL11A is a genetically and functionally validated regulator of γ-globin expression and a prime candidate for targeted therapy aimed at induction of HbF in individuals with SCD. Curative treatment for SCD can be attained with hematopoietic stem cell transplantation (HSCT). Graft failure and transplant-related mortality contribute to the significant complications associated with allogeneic HSCT in SCD. Favorable outcomes in SCD are largely dependent on the availability of matched sibling donors and the incidence of graft failure and graft versus host disease (GVHD). Fewer than 10% of SCD patients have unaffected HLA-matched sibling potential donors. Gene therapy for the hemoglobinopathies offers the clear advantage of eliminating the risk of GVHD and the need to identify suitable stem cell donors by the use of autologous cells. Targeting BCL11A in SCD holds the significant advantage that adequate knockdown of BCL11A in erythroid cells derived from gene-modified hematopoietic stem cells (HSCs) will increase HbF expression while concurrently reducing expression of mutant HbS. Since hemoglobin polymerization in sickle red cells is highly dependent on the intracellular concentration of HbS and is strongly inhibited by HbF, vectors effectively targeting BCL11A should prevent the cellular phenotype of sickle-containing red cells. Reduced hemoglobin polymerization would thus lead to a pronounced increase in the red cell half-life in vivo. We have recently shown that that use of erythroid-specific expression of microRNA adapted shRNAs (shRNAmiR) targeting BCL11A effectively induces HbF in human erythroid cells derived from transduced HSCs, largely attenuating the hematologic effects of SCD in a murine model. Based on mathematical modeling and preclinical data, we predict that transduction of human HSCs will reduce red cell sickling in a range that will significantly attenuate the SCD phenotype. Based on these data, we propose a pilot/feasibility study in a limited cohort of SCD patients determine the applicability of this approach.

在镰状细胞病（SCD）和β-丘脑中诱导胎儿血红蛋白（HBF）是一种极其一种极其极为极端的 可以改善两种疾病严重程度的有前途的方法。最近的分子研究揭示了新的 包括BCL11A在内的人类胎儿到成年血红蛋白转换的调节剂。 Bcl11a是一个普遍的， 通过功能验证的γ-球蛋白表达调节剂和针对目标治疗的主要候选者 SCD个体中HBF的诱导。 SCD的治疗疗法可以与造血茎相连 细胞移植（HSCT）。移植失败和与移植相关的死亡率有助于显着 SCD中与同种异体HSCT相关的并发症。 SCD中的有利结果在很大程度上取决于 匹配的兄弟姐妹供体的可用性以及移植失败和移植与宿主疾病的事件 （GVHD）。不到10％的SCD患者没有受到影响的HLA匹配兄弟姐妹潜在供体。基因 血红蛋白疗法的疗法具有消除GVHD风险的明显优势和需要 通过使用自体细胞来识别合适的干细胞供体。 SCD中的BCL11A具有重要意义 优势在源自基因改性造血的红细胞细胞中Bcl11a的足够敲低 干细胞（HSC）将增加HBF表达，同时还原突变HB的表达。自从 镰状细胞中的血红蛋白聚合高度依赖于HBS的细胞内浓度和 HBF强烈抑制 含有镰刀的红细胞。因此，血红蛋白聚合减少将导致明显增加 红细胞半衰期在体内。我们最近表明，microRNA的红细胞特异性表达 针对BCL11A的适应性shRNA（Shrnamir）有效地诱导了源自人类红细胞的HBF 转导HSC，在很大程度上削弱了鼠模型中SCD的血液学作用。基于 数学建模和临床前数据，我们预测人类HSC的翻译将减少红细胞 在会大大减弱SCD表型的范围内可恶。基于这些数据，我们提出了 在有限的SCD患者队列中，试点/可行性研究确定了这种方法的适用性。