Safety and Efficacy of the Lentiviral Vector in Gene Therapy of Beta-thalassemia Patients

This is a non-randomized, open-label, single-dose study. The aim of this study is to evaluate the safety and efficacy of the treatment with lentiviral vector encoding βA-T87Q-globin gene transduced autologous hematopoietic stem cells transfusion in subjects with transfusion-dependent β-thalassemia.


Eligibility Criteria:
Inclusion Criteria:

* Male or female age between 3-35 years
* Diagnosis of transfusion-dependent β-thalassemia and a history of at least 100 mL/kg/year of pRBCs or ≥8 transfusions of pRBCs per year for the prior 2 years
* Documented baseline, or pretransfusion, Hb level≤7 g/dL
* Karnofsky performance status ≥70 for subjects≥16 years of age; Lansky performance status of ≥70 for subjects\<16 years of age
* Eligible to undergo auto-HSCT
* Willing and able to follow the research procedures and conditions, with good compliance
* Willing to receive at least the 2 years follow-up and maintain detailed medical records, including transfusion history
* Subject and/or legal guardians voluntarily participated in this clinical trial and signed the informed consent form, and can complete all follow-ups in accordance with the protocol requirements

Exclusion Criteria:

* Presence of clear contraindications for hematopoietic stem cell collection
* Diagnosis of composite α thalassemia
* A white blood cell (WBC) count \<3×10\^9/L, and/or platelet count \<100×10\^9/L not related to hypersplenism
* Subjects with severe iron overload at the time of screening: severe iron overload of the liver showed by MRI, serum ferritin ≥ 5000 ng/mL, or moderate to severe iron overload of the heart
* Any prior or current malignancy or myeloproliferative or significant immunodeficiency disorder
* Meet the criteria for allo-HSCT and with an identified willing donor with a full HLA match
* Prior receipt of gene therapy or allo-HSCT
* Subjects with any severe active fungal, bacterial, viral, tuberculosis or other infection, including active hepatitis B (defined as serum HBV-DNA ≥2000 IU/ml), active hepatitis C virus, HCV) infection, human immunodeficiency virus (HIV) antibody-positive or active syphilis patients, etc.
* Immediate family member (i.e. parent or siblings) with a known Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome and familial adenomatous polyposis)
* Diagnosis of a significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study
* History of major organ damage including:

  1. Liver function test suggest AST or ALT levels \>3× upper limit of normal (ULN);
  2. Total serum bilirubin value \>2.5×ULN;if combined with Gilbert syndrome, total bilirubin \>3×ULN and direct bilirubin value \>2.5×ULN;
  3. History of bridging fibrosis, cirrhosis;
  4. Left ventricular ejection fraction \<45%;
  5. New York Heart Association (NYHA) class III or IV congestive heart failure;
  6. Severe arrhythmia requiring medical treatment;
  7. Uncontrolled hypertension or unstable angina pectoris;
  8. Myocardial infarction or bypass or stent surgery within 12 months before drug administration;
  9. Valvular disease with clinical significance;
  10. Baseline calculated eGFR\<60mL/min/1.73m2;
  11. Pulmonary function: FEV1/FVC\<60% and/or diffusion capacity of carbon monoxide (DLco) \<60% of prediction;
  12. Evidence of clinically significant pulmonary hypertension requiring medical intervention.
* Uncorrectable coagulation dysfunction or history of severe bleeding disorder
* Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician
* Known allergy to clinical trial drug (plerixafor or G-CSF or busulfan) or ingredient(DMSO etc.)
* Participated in other clinical studies within 3 months prior to screening
* Inoculated live vaccine within 6 weeks prior to screening
* Pregnancy or breastfeeding women; Subjects or their sexual partners were unable to take medically recognized effective contraceptive measures during the 27-month study period
* The subjects or their parents would not comply with the study procedures outlined in the protocol
* The subjects received hydroxyurea or thalidomide or hypomethylating drugs within 3 months before hematopoietic stem cell collection
* Patients considered to be ineligible for the study by the investigator for reasons other than the above