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可治愈镰状细胞 疾病(SCD)，但通常仅适用于10%-15%的匹配 亲属捐赠者。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)方法在有限的临床试验中可用。然而，问题仍然存在。 关于镰状Hb(HBS)矫正或胎儿血红蛋白(HBF)诱导的水平和程度 基因修饰干细胞的植入需要达到治愈的目的。尽管有多年的经验 羟基尿素(HU)诱导高血压性心衰，并对基线进行流行病学研究 HbF水平与症状的相关性，尚不清楚需要什么水平的HbF才能显著 SCD并发症的改善，或不均匀分布时可容忍的百分比HBS 遍及红细胞(RBC)。 我们必须对接受过基因治疗的患者进行功能性评估， 而不是仅仅依靠Hb档案来评估反应。SCD血液的质量或流变学 明显异常，这些异常与疾病并发症密切相关。这个 任何基于基因的SCD治疗的目标都应该是使每个患者的血液流变学正常化到 具有镰状细胞特征(SCT)的个体的最低水平。非根治性疗法，如胡和 输血缓解SCD患者的症状和改善血液流变学，尽管对SCT无效 价值观。我们建议首先在SCD患者中验证流变学生物标志物，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 接受异基因造血干细胞移植的SCD患者的生物标记物表现，询问我们的生物标记物 预测与治愈相一致的无症状结果。最后，我们将应用这些经过验证的 以基因治疗为基础的患者的生物标志物。不能实现的战略 可与HbAS或成功的异基因HSCT相媲美的流变学矫正可能还需要进一步 优化。