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: 10179447
• 负责人: DAVID A WILLIAMS
• 金额: $ 19.68万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179447
• 关键词: Adult; Allogenic; Architecture; Attenuated; Autologous; Biocompatible Materials; 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; Hematology; 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; Toxic effect; Transgenes; Transplantation; Virus; base; beta Thalassemia; chronic graft versus host disease; clinical effect; cohort; curative treatments; cytotoxicity; disease phenotype; donor stem cell; 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-地中海贫血中，胎儿血红蛋白（HbF）的诱导是非常重要的

项目成果

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

• DOI: 10.1056/nejmoa2029392
• 发表时间: 2021-01-21
• 期刊: The New England journal of medicine
• 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
• 通讯作者: Williams DA

DROSHA Knockout Leads to Enhancement of Viral Titers for Vectors Encoding miRNA-Adapted shRNAs.

• DOI: 10.1016/j.omtn.2018.07.002
• 发表时间: 2018-09-07
• 期刊: Molecular therapy. Nucleic acids
• 作者: Park HH;Triboulet R;Bentler M;Guda S;Du P;Xu H;Gregory RI;Brendel C;Williams DA
• 通讯作者: Williams DA