a phase 1 study of gene-modified autologous hematopoietic stem cell (bd211) treating β-thalassemia major

Conditions: β-thalassemia

Summary: this study will be intented to evaluate the safety, tolerability, and engraftment efficacy after myeloablative preconditioning and transplantation of autologous cd34+ hematopoietic stem cells transduced with a lentiviral vector encoding the human βa-t87q-globin gene in patients with transfusion-dependent (tdt) β-thalassemia.

this is an open-label, single-dose study of bd211 in patients with transfusion-dependent β-thalassemia aged 3 to 35 years. it is estimated that 9 subjects will be enrolled. bd211 is a gene modified gene therapy product designed to produce healthy β-globin in red blood cells in beta-thalassemia patients. the total follow-up duration was 18 months, the safe endpoints and effectiveness endpoints will be used to assess the safety and efficacy profiles in patients with transfusion-dependent β-thalassemia.

Eligibility criteria:
inclusion criteria: 1. participants aged 3 years (inclusive) to 18 years (exclusive), with no gender restrictions. 2. parents/legal guardians have fully understood and voluntarily signed a written informed consent form; and it is recommended that children aged 8 and above be involved in the decision to participate in this clinical trial and obtain a written consent form. 3. transfusion-dependent β-thalassemia patients. "transfusion-dependent" is defined as: requiring at least 100 ml/kg of packed red blood cells annually; the genotype can be β0/β0, β0/β+, or β+/β+, diagnosed through hemoglobin studies. 4. eligible for allogeneic hematopoietic stem cell transplantation, but without a donor or those refusing to undergo allogeneic hematopoietic stem cell transplantation. 5. have undergone symptomatic treatment for at least the past 2 years and have retained medical records including transfusion history. 6. stable condition and maintained an appropriate iron chelation regimen. 7. good status of organ function. 8. good compliance from the individual and parents/legal guardians, willing to adhere to visit schedules, trial plans, laboratory tests, and other trial procedures as stipulated in this protocol. 9. willing to participate in long-term follow-up research. exclusion criteria: 1. has a fully hla-matched hematopoietic stem cell donor and is willing to receive a fully hla-matched hematopoietic stem cell transplant. enrollment is otherwise only advised after review by the safety review committee. 2. positive for antibodies against human immunodeficiency virus 1/2 (hiv-1/hiv-2), treponema pallidum (tp) specific antibodies, human t-lymphotropic virus 1 or 2 (htlv-1/htlv-2) antibodies, and vesicular stomatitis virus g (vsv-g). 3. positive for hepatitis b virus (hbv) hbsag or hbv-dna; hepatitis c virus (hcv) hcab positive; positive nucleic acid test for epstein-barr virus (ebv) or cytomegalovirus (cmv). 4. severe active bacterial, viral, fungal, malarial, or parasitic infections. 5. has had, or currently has, a malignant, myeloproliferative, or immunodeficiency disorder. 6. direct relatives with known or suspected hereditary cancer syndromes (including but not limited to breast cancer, colorectal cancer, ovarian cancer, prostate cancer, and pancreatic cancer). 7. autoimmune diseases that could result in transfusion difficulties. 8. major organ diseases or abnormal lab tests, including: 1. liver cirrhosis, fibrosis, or active hepatitis, and/or abnormal liver function tests (serum total bilirubin (tbil) ≥ 1.5x upper limit of normal (uln); alanine aminotransferase (alt) and aspartate aminotransferase (ast) ≥ 2.5x uln; alkaline phosphatase ≥ 2.5x uln). 2. heart disease, or left ventricular ejection fraction (lvef) \< 60%. 3. kidney diseases, or serum creatinine ≥ 1.5uln, creatinine clearance rate \< 30% of the normal level (measured or calculated by the cockcroft-gault equation). 4. endocrine disorders, such as insulin-dependent diabetes, hyperthyroidism, or hypothyroidism. 5. severe iron overload, serum ferritin ≥ 5000 ng/ml. 6. cardiac t2\* \< 20 ms, and/or liver iron content (lic) ≥ 15mg/g liver weight by mri. 7. significant pulmonary hypertension diagnosed clinically according to guidelines, requiring clinical medical intervention. 9. uncorrected bleeding disorders. 10. severe psychiatric disorders. 11. peripheral blood white cell (wbc) count \< 3x10\^9/l or platelets count \< 120x10\^9/l. 12. received hydroxyurea treatment within the last 3 months before stem cell collection. 13. used erythropoiesis-stimulating agents within the 3 months prior to hsc collection. 14. history of allogeneic transplantation. 15. previously received any type of gene and/or cell therapy. 16. participating in another clinical trial and is within a 30-day screening period. 17. has contraindications to anesthesia. 18. has contraindications to hematopoietic stem cell collection. 19. allergic to the investigational drug or its excipients. 20. any other conditions determined by the investigator as unsuitable for participation in this clinical trial.