A Phase 1 Study of Gene-modified Autologous Hematopoietic Stem Cell (BD211) Treating β-thalassemia Major

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.

Inclusion criteria

• Participants aged 3 years (inclusive) to 18 years (exclusive), with no gender restrictions.
• 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.
• 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.
• Eligible for allogeneic hematopoietic stem cell transplantation, but without a donor or those refusing to undergo allogeneic hematopoietic stem cell transplantation.
• Have undergone symptomatic treatment for at least the past 2 years and have retained medical records including transfusion history.
• Stable condition and maintained an appropriate iron chelation regimen.
• Good status of organ function.
• 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.
• Willing to participate in long-term follow-up research.

Exclusion criteria

• 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.
• 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).
• 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).
• Severe active bacterial, viral, fungal, malarial, or parasitic infections.
• Has had, or currently has, a malignant, myeloproliferative, or immunodeficiency disorder.
• 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).
• Autoimmune diseases that could result in transfusion difficulties.
• Major organ diseases or abnormal lab tests, including:

• 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).
• Heart disease, or Left Ventricular Ejection Fraction (LVEF) < 60%.
• Kidney diseases, or serum creatinine ≥ 1.5ULN, creatinine clearance rate < 30% of the normal level (measured or calculated by the Cockcroft-Gault equation).
• Endocrine disorders, such as insulin-dependent diabetes, hyperthyroidism, or hypothyroidism.
• Severe iron overload, serum ferritin ≥ 5000 ng/mL.
• Cardiac T2* < 20 ms, and/or liver iron content (LIC) ≥ 15mg/g liver weight by MRI.
• Significant pulmonary hypertension diagnosed clinically according to guidelines, requiring clinical medical intervention.
• Uncorrected bleeding disorders.
• Severe psychiatric disorders.
• Peripheral blood white cell (WBC) count < 3x10^9/L or platelets count < 120x10^9/L.
• Received hydroxyurea treatment within the last 3 months before stem cell collection.
• Used erythropoiesis-stimulating agents within the 3 months prior to HSC collection.
• History of allogeneic transplantation.
• Previously received any type of gene and/or cell therapy.
• Participating in another clinical trial and is within a 30-day screening period.
• Has contraindications to anesthesia.
• Has contraindications to hematopoietic stem cell collection.
• Allergic to the investigational drug or its excipients.
• Any other conditions determined by the investigator as unsuitable for participation in this clinical trial.