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

Evaluation of the Safety and Efficacy of KL003 Gene Therapy in Patients With Transfusion-dependent β-thalassemia With No Conditioning Regimen

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.

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