Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling.
Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling.
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DOI：
10.1038/s41467-023-40923-5
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发表时间：
2023-09-20
影响因子：
16.6
通讯作者：
Higgins, John M.
中科院分区：
文献类型：
--
作者：
De Souza, Daniel C.;Hebert, Nicolas;Esrick, Erica B.;Ciuculescu, M. Felicia;Archer, Natasha M.;Armant, Myriam;Audureau, Etienne;Brendel, Christian;Di Caprio, Giuseppe;Galacteros, Frederic;Liu, Donghui;Mccabe, Amanda;Morris, Emily;Schonbrun, Ethan;Williams, Dillon;Wood, David K.;Williams, David A.;Bartolucci, Pablo;Higgins, John M.
我们先前报道了BCL 11 A表达的转录后基因沉默（NCT 03282656）逆转胎儿至成人血红蛋白转换的初步临床结果。该方法的目标是增加胎儿血红蛋白（HbF）表达，同时协调地减少镰状血红蛋白（HbS）表达。由此产生的组合效应应证明在较低生理氧值下有效抑制HbS聚合，从而减轻疾病并发症。在这里，我们报告了对BCL 11 A分子靶向的患者进行探索性单细胞分析的结果，并将结果与接受当前标准治疗的羟基脲（HU）治疗的患者的细胞进行比较。我们使用单细胞测定来评估9名基因治疗试验受试者（BCLshmiR，中位HbF% = 27.9）的RBC中的HbF、HbS、氧饱和度和血红蛋白聚合物含量，并将其与10名显示出高且相当水平的HbF的HU治疗受试者（HU高应答者，中位HbF% = 27.0）进行比较。所有BCL 11 A患者均达到NCT 03282656的主要终点，其定义为输注后7周内中性粒细胞绝对计数连续3天≥ 0.5 × 109个细胞/L。单RBC HbF和HbS的流式细胞术评估显示，在BCLshmiR中相对于HU高应答者，具有最易镰状化的高HbS%的RBC较少：在BCLshmiR中HbS%>70%的RBC的中值为42%，在HU高应答者中为61%（p = 0.004）。BCLshmiR受试者在较低的生理氧分压下也表现出更多的RBC对HbS聚合的抗性：中位数32%对HU高应答者中的25%（p = 0.006）。基因治疗诱导的BCL 11 A下调逆转了胎儿至成人血红蛋白的转换，并诱导临床试验受试者中的RBC具有较高的HbF%、较低的HbS%和对脱氧诱导聚合的更大抵抗力，与高反应性羟基脲治疗受试者队列相比。作者完整报告了一项初步临床试验（NCT 03282656）的主要终点数据，该试验使用BCL 11 A表达的转录后基因沉默来逆转镰状细胞病中胎儿至成人血红蛋白的转换。他们开发了新的单细胞流式细胞术和微流体技术来预测HbF诱导的功效，并表明这些患者的红细胞比来自羟基脲反应患者的红细胞对脱氧诱导的聚合表现出更大的抵抗力。
We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT 03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCLshmiR, median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT 03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 109 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCLshmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCLshmiR vs. 61% in HU High Responders (p = 0.004). BCLshmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects. The authors report in full the primary endpoint data of a pilot clinical trial (NCT 03282656) that used post-transcriptional gene silencing of BCL11A expression to reverse the fetal to adult hemoglobin switch in sickle cell disease. They develop new single-cell flow cytometry and microfluidic techniques to predict the efficacy of HbF induction and show that red blood cells from these patients exhibit greater resistance to deoxygenation-induced polymerization than red blood cells from hydroxyurea-responsive patients.
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影响因子：
6.5
作者：
Ngo DA;Aygun B;Akinsheye I;Hankins JS;Bhan I;Luo HY;Steinberg MH;Chui DH
通讯作者：
Chui DH
影响因子：
--
作者：
Eaton, W A;Hofrichter, J
通讯作者：
Hofrichter, J
影响因子：
3.5
作者：
Keren, David F.;Hedstrom, Deborah;Bak, Richard
通讯作者：
Bak, Richard
影响因子：
10.1
作者：
Bernaudin, Francoise;Dalle, Jean-Hugues;Socie, Gerard
通讯作者：
Socie, Gerard
DOI：
10.1073/pnas.1914056116
发表时间：
2019-12-10
影响因子：
11.1
作者：
Di Caprio, Giuseppe;Schonbrun, Ethan;Higgins, John M.
通讯作者：
Higgins, John M.