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.

镰状细胞病 (SCD) 和 β-地中海贫血中胎儿血红蛋白 (HbF) 的诱导是一种极为罕见的疾病。 最近的分子研究揭示了减轻这两种疾病严重程度的有希望的方法。 BCL11A 是人类胎儿到成人血红蛋白转换的调节因子。 经过功能验证的 γ-珠蛋白表达调节剂，是靶向治疗的主要候选者 SCD 患者中 HbF 的诱导可以通过造血干细胞来实现 SCD 的治愈性治疗。 细胞移植（HSCT）导致移植失败和移植相关的死亡率。 SCD 中与同种异体 HSCT 相关的并发症在很大程度上取决于 SCD 的良好结果。 匹配的同胞供体的可用性以及移植失败和移植物抗宿主病的发生率 (GVHD) 不到 10% 的 SCD 患者具有未受影响的 HLA 匹配的兄弟姐妹潜在捐赠者。 血红蛋白病的治疗具有明显的优势，可以消除 GVHD 的风险，并且不需要 通过使用自体细胞靶向 BCL11A 在 SCD 中识别合适的干细胞供体具有重要意义。 优点是在源自基因修饰的造血系统的红系细胞中充分敲低 BCL11A 干细胞 (HSC) 将增加 HbF 表达，同时减少突变型 HbS 的表达。 镰状红细胞中的血红蛋白聚合高度依赖于细胞内 HbS 的浓度和 被 HbF 强烈抑制，有效靶向 BCL11A 的载体应能阻止 HbF 的细胞表型 含镰状红细胞的血红蛋白聚合减少将导致血红蛋白显着增加。 我们最近证明，利用红细胞特异性表达的 microRNA 可以缩短体内红细胞的半衰期。 靶向 BCL11A 的改编 shRNA (shRNAmiR) 可有效诱导来自以下来源的人红系细胞中的 HbF 转导 HSC，在小鼠模型中很大程度上减弱了 SCD 的血液学影响。 根据数学模型和临床前数据，我们预测转导人类造血干细胞将减少红细胞 根据这些数据，我们提出了一个将显着减弱 SCD 表型的范围。 在有限的 SCD 患者群体中进行的试点/可行性研究确定了该方法的适用性。