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 疾病（SCD），但通常仅适用于10-15%的具有匹配的 相关捐赠者幸运的是，有可行的基因治疗（基于慢病毒）和基因编辑 （基于CRISPR/Cas9的）方法在有限的临床试验中可用。然而， 关于镰状血红蛋白（HbS）校正水平或胎儿血红蛋白（HbF）诱导和程度 移植基因修饰的干细胞来达到治愈的目的。尽管有多年的经验 使用羟基脲（HU）进行药物HbF诱导，以及基线的流行病学研究 HbF水平与症状相关，尚不清楚什么水平的HbF是需要显着 SCD并发症的改善，或当分布不均匀时可以耐受的%HbS 红细胞（RBC）。 我们必须对接受过基因治疗的患者进行功能评估， 而不是仅仅依靠Hb谱来评估反应。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。的 任何基于基因的SCD治疗的目标应该是使每个患者的血液流变学正常化， 至少是镰状细胞性状（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，改善血液流变学，但对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， 用于区分HbAA、HbAS和HbSS样品的生物标志物。接下来，我们将评估 接受alloHSCT的SCD患者的生物标志物性能，询问我们的生物标志物是否 预测无症状的结果与治愈一致。最后，我们将应用这些经过验证的 生物标志物对接受基因治疗的患者的影响。无法实现的战略 与HbAS或成功的alloHSCT相当的流变学校正可能需要进一步研究。 优化.