Gene Therapy for Patients With Transfusion-Dependent β-Thalassemia

This is a single-arm, open-label, single-dose, single site study in approximately 6 subjects ≥12 and ≤45 years of age with TDT. Subjects must have TDT with a transfusion history of at least 100mL/kg/year of packed red blood cells (pRBCs) or 8 transfusions of pRBCs per year in the past 2 years before enrollment.

Stage 1: Screening to determine eligibility for treatment: Subjects with previously known β0/β0 or non-β0/β0 genotypes are eligible for screening.

Stage 2: Autologous CD34+ cell collection, HGI-001 Injection manufacture and disposition: Each subject will undergo HSC mobilization with a granulocyte-colony stimulating factor (G-CSF) and plerixafor. Peripheral blood mononuclear cells (PBMCs) will be collected by apheresis. A total of 2 mobilization cycles may be performed if needed and each mobilization cycle may include up to 3 days for apheresis.

Stage 3: Myeloablative conditioning and infusion of HGI-001 Injection (Day 0)

: the subject will undergo myeloablative conditioning with busulfan. After completion of the 4-day course of busulfan, there must be a minimum of 48 hours of washout period before administration of HGI-001 Injection. On study Day 0, after thawing, the HGI-001 Injection will be administered via intravenous (IV) infusion at a dose of >4.0 × 106 CD34+ cells/kg.

Stage 4: Follow-up, through engraftment and up to 12 months after HGI-001 Infusion: Subjects will be followed up daily in the transplant unit for adverse events (AEs), and laboratory parameters will be followed up to monitor bone marrow engraftment. The subject will be discharged from the transplant unit once the subject is considered clinically stable.

The goal during the follow-up period is to maintain hemoglobin (Hb) ≥9 g/dL. Transfusions should be avoided for patients with Hb ≥9 g/dL, unless the transfusion need is medically justified (e.g., as a pre-requirement for surgery).

Inclusion criteria

• Subjects between 12 and 45 years of age at the time of consent and are able to provide written informed consent.
• Diagnosis of TDT, also known as β-thalassemia major, without genotype restriction, and a valid test report can be provided.
• A history of at least 100 mL/kg/year of pRBCs transfusion or ≥ 8 transfusions of pRBCs per year for previous 2 years.
• Sufficient blood transfusion for at least 3 months before screening (transfusion records can be provided), and Hb is maintained ≥9.0 g/dL before each transfusion.
• The level of ferritin <5000ng/mL; Cardiac magnetic resonance imaging (MRI) T2 and liver MRI T2 findings suggest iron overload at a moderate level or below.
• Clinically stable, and eligible for autologous hematopoietic stem cell transplant (auto-HSCT).
• Adequate organ function for the conditioning with busulfan.

Exclusion criteria

• Uncorrected bleeding disorder;
• Uncontrolled epilepsy or mental disorders;
• Received hydroxyurea, ruxolitinib, decitabine, or cytarabine within 3 months prior to enrollment;
• Usage of psychoactive substance, drug, or alcohol abuse within six months prior to screening.
• Pulmonary hypertension without effective intervention.
• Persistent toxicity (≥ CTCAE grade 2) induced by previous treatment.
• Positive for anti-RBC antibodies.
• Positive for hepatitis B surface antigen (HBsAg) and HBV DNA copy number > upper limit of normal (ULN) (HBV DNA test not required for patients negative for HBsAg), positive for hepatitis C virus (HCV) antibody, unless HCV RNA is negative (HCV RNA-negative subjects are not excluded), positive human immunodeficiency virus (HIV), or positive for Treponema pallidum antibody (TP-Ab) (subjects who are positive for the antibody due to vaccination can be enrolled).
• Has or has had malignant tumors or myeloproliferative disease or immunodeficiency disease;
• Clinically significant and active bacterial, viral, fungal, or parasitic infection.