Combinatorial targeting of epigenome-modifying enzymes with decitabine and RN-1 synergistically increases HbF.
Combinatorial targeting of epigenome-modifying enzymes with decitabine and RN-1 synergistically increases HbF.
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DOI：
10.1182/bloodadvances.2022009558
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发表时间：
2023-08-08
期刊：
影响因子：
7.5
通讯作者：
Lavelle, Donald
中科院分区：
文献类型：
--
作者：
Ibanez, Vinzon;Vaitkus, Kestis;Zhang, Xu;Ramasamy, Jagadeesh;Rivers, Angela E.;Saunthararajah, Yogen;Molokie, Robert;Lavelle, Donald
DNMT 1和LSD 1的药理学抑制剂的联合给药协同增加健康狒狒的HbF。该药物组合在非贫血和贫血（抽血）狒狒中诱导高水平的HbF和F细胞。胎儿血红蛋白（HbF）水平升高可减轻镰状细胞病（SCD）的症状并延长患者的寿命。由于骨髓移植和基因治疗技术的治疗策略对大量患者仍然不可用，因此开发一种安全有效的增加HbF的药物治疗为疾病干预提供了最大的潜力。尽管羟基脲可增加HbF，但相当一部分患者未能表现出充分的应答。DNA甲基转移酶（DNMT 1）和赖氨酸特异性脱甲基酶1A（LSD 1）的药理学抑制剂，2个表观基因组修饰酶与多蛋白辅阻遏物复合物招募到受抑制的γ-珠蛋白基因，是体内HbF的强大诱导剂。这些抑制剂的血液学副作用限制了可行的临床暴露。我们评估了联合使用这些药物是否可以减少暴露于任何单一药物的剂量和/或时间，以最大限度地减少不良反应，同时实现HbF的累加或协同增加。DNMT 1抑制剂地西他滨（0.5 mg/kg/天）和LSD 1抑制剂RN-1（0.25 mg/kg/天）每周联合给药2天，在健康狒狒中产生F细胞、F网织红细胞和γ-珠蛋白信使RNA的协同增加。在健康、非贫血和贫血（抽血）狒狒中观察到HbF和F细胞大幅增加。因此，靶向表观基因组修饰酶的组合疗法可能是一种有用的策略，用于产生HbF的更大增加，以改变SCD的临床过程。
The combined administration of pharmacological inhibitors of DNMT1 and LSD1 synergistically increase HbF in healthy baboons. The drug combination induced high levels of HbF and F-cells in both nonanemic and anemic (phlebotomized) baboons. Increased fetal hemoglobin (HbF) levels reduce the symptoms of sickle cell disease (SCD) and increase the lifespan of patients. Because curative strategies for bone marrow transplantation and gene therapy technologies remain unavailable to a large number of patients, the development of a safe and effective pharmacological therapy that increases HbF offers the greatest potential for disease intervention. Although hydroxyurea increases HbF, a substantial proportion of patients fail to demonstrate an adequate response. Pharmacological inhibitors of DNA methyltransferase (DNMT1) and lysine-specific demethylase 1A (LSD1), 2 epigenome-modifying enzymes associated with the multiprotein corepressor complex recruited to the repressed γ-globin gene, are powerful in vivo inducers of HbF. The hematological side effects of these inhibitors limit feasible clinical exposures. We evaluated whether administering these drugs in combination could reduce the dose and/or time of exposure to any single agent to minimize adverse effects, while achieving additive or synergistic increases in HbF. The DNMT1 inhibitor decitabine (0.5 mg/kg per day) and the LSD1 inhibitor RN-1 (0.25 mg/kg per day) administered in combination 2 days per week produced synergistic increases in F-cells, F-reticulocytes, and γ-globin messenger RNA in healthy baboons. Large increases in HbF and F-cells were observed in healthy, nonanemic, and anemic (phlebotomized) baboons. Combinatorial therapy targeting epigenome-modifying enzymes could thus be a useful strategy for producing larger increases in HbF to modify the clinical course of SCD.
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DOI：
10.2147/dddt.s81911
发表时间：
2015
期刊：
Drug design, development and therapy
影响因子：
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作者：
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