Clinical Study on the Safety and Efficacy of a Single Intravenous Dose of CRISPR/Cas9-Edited Autologous CD34+ Hematopoietic Stem/Progenitor Cells (BRL-101) in the Treatment of Sickle Cell Disease
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 5
- 主要终点
- Proportion of stem cell engrafted subjects
研究概览
简要总结
This is a single center, non-randomized, open label, single-dose study in subjects with Sickle Cell Disease (SCD). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) (BRL-101).
详细描述
This clinical trial is a single-arm, single-dose, single center, open-label study without dose escalation. The primary objective is to explore the safety of the study drug in SCD. Myeloablative conditioning and administration for the remaining subjects can only be started after the first subject completes dosing and safety observation and assessment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 35 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Fully understood this study and voluntarily signed the written informed consent form.
- •Aged between 3 and 35 years.
- •Be diagnosed with Sickle Cell Disease (SCD), with a genotype of βS/βS, βS/β+ or βS/β
- •A Lansky/Karnofsky Performance Status (LPS) score of ≥
- •Suitable for autologous hematopoietic stem cell transplantation.
- •Have good compliance and are willing to adhere to visit schedules, trial protocols, laboratory tests, and other trial procedures.
- •Agree to participating in long-term follow-up studies.
- •Subjects of childbearing potential must use effective contraception for at least 6 months following cell reinfusion during the study.
排除标准
- •Subjects meeting any of the following criteria are not eligible for enrolment in the study:
- •Known contraindications, intolerance, or hypersensitivity to hematopoietic stem cell mobilizers, busulfan injection, or dimethyl sulfoxide (DMSO) or study drug-related components.
- •Eligible for allogeneic hematopoietic stem cell transplantation and have found HLA-identical donors.
- •Prior allo-HSCT, gene therapy or gene editing therapy.
- •Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
- •HbF level >15.0%, irrespective of concomitant treatment with HbF inducing treatments such as HU.
- •Treatment with regular RBC transfusions that, in the opinion of the investigator, cannot be interrupted after engraftment.
- •More than 10 unplanned hospitalizations or emergency department visits related to SCD in the 1 year before screening and the investigator considered this to be a significant chronic pain rather than an acute pain crisis.
- •A history of clinically significant transcranial Doppler (TCD) test abnormalities or test abnormalities in the opinion of the investigator.
- •History of untreated Moyamoya disease or presence of Moyamoya disease at screening that in the opinion of the investigator puts the subjects at the risk of bleeding.
- •The subject has participated in other clinical studies and used drugs within 3 months before screening.
- •White blood cell count < 3 × 109/L and/or platelet count < 100 × 109/L not due to hypersplenism as judged by the investigator.
- •INR > 1.5×ULN, APTT > 1.5×ULN.
- •Creatinine > 1.5 × ULN or endogenous creatinine clearance < 60 ml/min (calculated according to the Cockcroft-Gault formula, see Appendix 3).
- •ALT or AST> 3×ULN, or direct bilirubin value > 2.5×ULN.
- •Severe iron overload with serum ferritin ≥ 5000 ng/ml, liver iron > 15 mg Fe/g dry weight (or liver MRIT2* < 1.4 ms or > 588 Hz), or heart MRI-T2* < 10 ms.
- •LVEF < 50%.
- •DLco < 50% predicted (corrected haemoglobin or/and alveolar volume) or forced vital capacity (FVC) (measured/predicted) < 60% (For children for whom DLco could not be determined), or abnormal blood gas analysis (for younger children with undetectable ventilatory function only).
- •Hepatitis B virus surface antigen (HBsAg) positive or HBV-DNA positive; hepatitis C virus (HCV) antibody positive; human immunodeficiency virus (HIV) antibody positive; syphilis (TP) -specific antibody positive; Epstein-Barr virus EBV-DNA positive; cytomegalovirus CMV-DNA positive.
- •History of a significant bleeding disorder.
- •History or family history of malignancy or myeloproliferative disorder.
- •Any prior or current cardiovascular system diseases, such as congestive heart failure, arrhythmia, myocardial disease, valvular heart disease or pulmonary hypertension; cirrhosis, liver fibrosis or active hepatitis; central nervous system diseases or mental illness.
- •Presence of immune dysfunction or endocrine disorders, such as insulin-dependent diabetes mellitus, hyperthyroidism, or insufficiency.
- •Pregnant or breastfeeding females.
- •Any condition that, in the opinion of the investigator, would make participation in this clinical study inappropriate.
研究组 & 干预措施
BRL-101
Autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the BCL11A gene. Subjects will receive a single infusion of BRL-101.
干预措施: BRL-101 (Drug)
结局指标
主要结局
Proportion of stem cell engrafted subjects
时间窗: Within 42 Days After BRL-101 Infusion
Stem cell engraftment was defined as an absolute peripheral blood neutrophil count of ≥ 0.5 × 109/L for 3 consecutive days following BRL-101 intravenous infusion.
Frequency, severity, and relationship to BRL-101 of adverse events over 12 months following BRL-101 infusion.
时间窗: Within 12 Months After BRL-101 Infusion
Adverse events assessed according to NCI-CTCAE v5.0 criteria
Time to neutrophil engraftment
时间窗: Within 42 Days After BRL-201 Infusion
Defined as Day 1 of absolute peripheral blood neutrophil count ≥ 0.5 × 109/L for 3 consecutive days
次要结局
未报告次要终点