Rheology biomarkers for gene-based therapy

用于基因治疗的流变生物标志物

• 批准号: 10317537
• 负责人: Vivien Andrea Sheehan
• 金额: $ 35.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-23 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317537
• 关键词: Rheology; biomarkers; gene; based; therapy

Allogeneic hematopoietic stem cell transplant (alloHSCT) can provide a cure for sickle cell disease (SCD), but is typically available only to the 10-15% of patients who have a matched related donor. Fortunately, there are viable gene therapy (lentivirus based) and gene editing (CRISPR/Cas9 based) approaches available in limited clinical trials. However, questions remain regarding the level of sickle Hb (HbS) correction or fetal hemoglobin (HbF) induction and degree of engraftment of gene modified stem cells needed to achieve a cure. Despite years of experience with pharmacologic HbF induction with hydroxyurea (HU), and epidemiological studies of baseline HbF levels and symptom correlation, it is not known what level of HbF is needed for significant amelioration of SCD complications, or what %HbS can be tolerated when unequally distributed throughout the red blood cells (RBCs). It is essential that we functionally evaluate patients who have undergone gene-based therapy, rather than rely solely on Hb profiles to assess response. The quality, or rheology, of SCD blood is markedly abnormal, and these abnormalities correlate strongly with disease complications. The goal of any gene-based SCD cure should be to normalize blood rheology of each patient to at least the level of an individual with sickle cell trait (SCT). Non-curative therapies like HU and transfusion relieve symptoms and improve rheology in patients with SCD, although not to the SCT values. We propose to validate rheological biomarkers first in patients with SCD, testing the ability of biomarkers to differentiate HbAA, HbAS, and HbSS samples. Next, we will assess the biomarker performance in SCD patients who have undergone alloHSCT, asking if our biomarkers predict an asymptomatic outcome consistent with a cure. Finally, we will apply these validated biomarkers to patients treated with gene-based therapy. Strategies which do not achieve rheological correction comparable to HbAS or successful alloHSCT may need further optimization.

异基因造血干细胞移植（alloHSCT）可以治愈镰状细胞病 疾病（SCD），但通常仅适用于 10-15% 具有匹配的患者 相关捐助者。幸运的是，有可行的基因疗法（基于慢病毒）和基因编辑 （基于 CRISPR/Cas9）方法可用于有限的临床试验。然而，问题仍然存在 关于镰状血红蛋白 (HbS) 校正或胎儿血红蛋白 (HbF) 诱导的水平和程度 实现治愈所需的基因修饰干细胞的植入。尽管有多年的经验 使用羟基脲 (HU) 进行药理学 HbF 诱导，以及基线的流行病学研究 HbF 水平与症状相关，目前尚不清楚需要什么水平的 HbF 才能显着 SCD 并发症的改善，或者分布不均时可以耐受的 %HbS 整个红细胞（RBC）。 我们对接受基因治疗的患者进行功能评估至关重要， 而不是仅仅依靠 Hb 概况来评估反应。 SCD 血液的质量或流变学 明显异常，并且这些异常与疾病并发症密切相关。这 任何基于基因的 SCD 治愈的目标应该是使每位患者的血液流变学正常化至 至少具有镰状细胞特征（SCT）个体的水平。非治愈性疗法，如 HU 和 输血可缓解 SCD 患者的症状并改善流变学，但不适用于 SCT 价值观。我们建议首先在 SCD 患者中验证流变生物标志物，测试其能力 用于区分 HbAA、HbAS 和 HbSS 样本的生物标志物。接下来，我们将评估 接受 alloHSCT 的 SCD 患者的生物标志物表现，询问我们的生物标志物是否 预测与治愈一致的无症状结果。最后，我们将应用这些经过验证的 接受基因治疗的患者的生物标志物。未实现的策略 与 HbAS 或成功的 alloHSCT 相当的流变学校正可能需要进一步 优化。