evaluating safety and efficacy of lentiviral-transduced cd34+ hscs in β-thalassaemia patients.

Conditions: Β-thalassemia

Summary: this is a single-arm, open label, multi-center, single-dose phase 1 clinical trial in subjects with transfusion dependent β-thalassaemia. the study aims to evaluate the safety and efficacy of autologous lentiviral-transduced cd34+ human hematopoietic stem cells (hhscs) using the gene therapy product hgi-001.

the investigators will recruit transfusion-dependent β-thalassaemia patients and collect their autologous hematopoietic stem cells, which will be modified with the lentihbbt87q system to restore β-globin expression. after conditioning, the autologous hematopoietic stem cells with restored β-globin will be reinfused to the patients and followed up for two years to collect data.

Eligibility criteria:
inclusion criteria: 1. aged 6-35 years (inclusive), icf can be provided by the patient and/or legal guardian; 2. definitively diagnosed with severe tdt without genotype restriction (excluding patients with coexisting α-thalassemia), and a valid test report can be provided; 3. average transfusion volume \> 100 ml/kg/year or transfusion frequency \> 8 times/year within 2 years prior to enrollment； 4. at least 3 months of full volume transfusion (verification of blood transfusion records can be provided) prior to screening, and hb is maintained at ≥ 9.0 g/dl; 5. serum ferritin level less than 5000μg/l, with moderate or lower iron overload in the heart and liver as indicated by magnetic resonance imaging (mri t2\*), specifically liver mri t2\* greater than 1.4ms and cardiac mri t2\* greater than 10ms; 6. acceptable organ functions (including heart, liver, kidney, lung and coagulation functions), stable disease condition, and suitable for busulfan pre-treatment and hematopoietic stem cell (hsc) transplantation as judged by the investigator; 7. meets follow-up requirements, adheres to treatment arrangements, and is able to return to the hospital regularly to undergo various examinations within 2 years after reinfusion of hgi-001 injection. exclusion criteria: 1. patients with fully hla-matched donors; 2. having previously received gene therapy, gene editing therapy, or allogeneic hematopoietic stem cell transplantation; 3. uncorrected bleeding disorder; 4. uncontrolled epilepsy and mental illness; 5. within the past 3 months prior to enrollment, the use of luspatercept, hydroxyurea, ruxolitinib, thalidomide, decitabine, or ara-c has been administered； 6. psychoactive substance abuse, drug or alcohol abuse within 6 months prior to enrollment; 7. patients with pulmonary hypertension who have not been given effective intervention; 8. positive for anti-rbc antibodies in antibody screening; 9. hepatitis b surface antigen (hbsag) is positive and the hbv dna copy number is greater than the upper limit of the normal value of the detection unit (those who are negative do not need to test for hbv dna copy number), antibodies to hepatitis c virus (hcv) are positive, antibodies to human immunodeficiency virus (hiv) are positive, or antibodies to treponema pallidum (tp-ab) are positive (subjects who are positive due to vaccination are eligible for enrollment). additionally, the results of hepatitis b virus (hbv) dna testing, hepatitis c virus (hcv) rna testing, cytomegalovirus dna testing, and epstein-barr virus (ebv) dna testing are abnormal； 10. have or have had malignant tumors or myeloproliferative diseases or immunodeficiency disorders or autoimmune diseases; 11. have a first-degree relative with a history of or suspected hereditary cancer (including but not limited to hereditary breast and ovarian cancer, nonpolyposis colorectal cancer, and adenomatous polyposis); 12. severe bacterial, viral, fungal or parasitic infection; 13. other illnesses which render the subject unsuitable for participation (e.g., severe liver, kidney or heart disease); definition of severe liver and kidney disease: a. aspartate aminotransferase (ast), alanine aminotransferase (alt), or total bilirubin \> 3 × uln; b. liver magnetic resonance imaging (mri) indicates significant cirrhosis; c. liver biopsy indicates cirrhosis, severe fibrosis or active hepatitis (liver biopsy is only performed when liver mri indicates active hepatitis and significant fibrosis without evidence for cirrhosis); d. creatinine clearance \<60 ml/(min·1.73m\^2); 14. wbc \< 3 × 10\^9/l and/or plt \< 100 × 10\^9/l; 15. has diabetes, abnormal thyroid functions or other endocrine disorder; 16. participated in other interventional clinical studies within 4 weeks before the trial; 17. poor adherence or other conditions that renders the subject unsuitable for participation as judged by the investigator.

Keywords: β-thalassemia thalassemia genetic diseases, inborn hemoglobinopathies hematologic diseases anemia anemia, hemolytic anemia, hemolytic, congenital