Safety and Efficacy of Gene Modified Autologous Hematopoietic Stem Cells to Treat Transfusion-dependent Beta-thalassemia

Safety and Efficacy of Lentiviral Vector Transduction of β-globin Genetically Modified Autologous CD34+ Hematopoietic Stem Cells in Patients With Transfusion-dependent β-thalassemia

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 18 years. It is estimated that 10 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 24 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:

1. Ages 3 to 18 years old, including:

   The parents or legal guardians must be able to understand and provide ICFs. If available, it is strongly recommended that children aged ≥8 years in treatment decisions and obtain written ICFs and be clearly documented; Diagnosed as Transfusion Dependent β-thalassemia with any genotype (β0, β+, βE/β0, βS/S, βS/β0, βS/β+), confirmed the Hb analysis. No alfa chain genetic abnormalities. Subjects must stabilize and maintain an appropriate iron chelation regimen. Transfusion-dependent types are defined as requiring at least 100 mL/kg/ year of red blood cells (pRBCs).

2. No eligiblity for allogeneic hematopoietic stem cell transplantation.

3. The treatment of erythrocyte maturation agent luspatercept cannot be financially supported.

4. The subjects' parents/legal guardians must be willing and able to follow the study procedures in the study protocol.

5. Good organs' functions.

6. Having complete medical records including a history of blood transfusions testified subject received treatment and followed up for at least two years prior to screening .

Exclusion Criteria:

1. Availability of voluntary, fully HLA-matched hematopoietic cell donors, unless recommended for inclusion by the Monitoring Committee.

2. HIV-1 and HIV-2 were positive, and / or HTLV-1, HTLV-2 and VSV-G antibodies were positive.

3. An active bacterial, viral, fungal or parasitic infection.

4. Contraindicated for the extraction of bone marrow under anesthesia.

5. Any malignancy, myeloproliferative, or immunodeficient disease and relevant medical history.

6. Peripheral blood white blood cell (WBC) count < 3×10^9/L or platelet count < 120×10^9/L.

7. A history of allo-transplantation.

8. Erythropoietin was used within 3 months prior to HSC cell collection.

9. Immediate family members with known or suspected familial cancer syndromes (including but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers).

10. Subjects with a diagnosis of major mental illness may had a serious disability to participate in the study.

11. Active recurrent malaria.

12. Had autoimmune diseases that may make blood transfusions difficult.

13. History of major organ injury including:

    Liver disease, transaminase > 3 times the upper limit of normal. (If the liver biopsy does not reveal evidence of widespread bridging fibrosis, cirrhosis, or acute hepatitis, this indicator will not be used as a criterion for the exclusion); Widely bridging fibrosis, histopathological evidence of acute hepatitis or cirrhosis showed in liver biopsy Heart disease, left ventricular ejection fraction < 25%; Kidney disease, creatinine clearance < 30% normal level; Of severe iron overload, confirmed by the study doctor; An heart MRI detection of T2 * < 10 ms; Significant pulmonary hypertension needing clinical medical intervention.

14. There are bleeding diseases that have not been cured.

15. The subject involved with another clinical study in a 30-day screening period.

16. Allergic to the research drug and its excipients.

17. Prior treatment with any type of gene and/or cell therapy.

18. As assessed by the investigator, the subjects or their parents are unable to comply well with the study procedures per protocol.

19. Hydroxyurea treatment within 3 months prior to hematopoietic stem cell collection.

20. Had diseases that interfere with hematopoietic stem cells collections.

21. Any other conditions being ineligible for HSC transplantation determined by the investigator.