safety and efficacy of the lentiviral vector in gene therapy of beta-thalassemia patients

Conditions: Transfusion-dependent Beta-Thalassemia

Summary: 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

Keywords: beta-thalassemia hematopoietic stem-cell transplantation kl003 gene therapy no conditioning regimen