A Study Evaluating the Safety and Efficacy of LentiGlobin BB305 Drug Product in β-Thalassemia Major (Also Referred to as Transfusion-dependent β-Thalassemia [TDT]) and Sickle Cell Disease

Inclusion Criteria

• Be between 5 and 35 years of age, inclusive.
• Have severe SCD or transfusion dependent beta-thalassemia major, regardless of the genotype with the diagnosis confirmed by Hb studies. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed red blood cells (pRBCs).
• Be eligible for allogeneic hematopoietic stem cell transplant (HSCT) based on institutional medical guidelines, but without a matched related donor.
• Be willing and able, in the Investigator's opinion, to comply with the study procedures outlined in the study protocol.
• Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.

Participants with severe SCD also must:

• Have failed to achieve adequate clinical benefit following hydroxyurea treatment with sufficient dosage, for at least 4 months unless this treatment was not indicated or not well tolerated.
• Have 1 or more of the following poor prognostic risk factors:
• Recurrent vaso occlusive crises (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program).
• Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions).
• Stroke without any severe cognitive disability.
• Osteonecrosis of 2 or more joints.
• Anti-erythrocyte alloimmunization (>2 antibodies).
• Presence of sickle cell cardiomyopathy documented by Doppler echocardiography.
• Acute chest syndrome (at least 2 episodes) defined by an acute event with pneumonia-like symptoms (e.g., cough, fever [>38.5°C], acute dyspnea, expectoration, chest pain, findings upon lung auscultation, tachypnea, or wheezing) and the presence of a new pulmonary infiltrate. Participants with a chronic oxygen saturation 170 cm/sec]; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease) may be enrolled only with approval by the Comite de Surveillance after review of safety and efficacy data from >or= 2 SCD participants without cerebral vasculopathy treated with LentiGlobin BB305 Drug Product

Exclusion Criteria

• Availability of a willing 10 /10 matched human leukocyte antigen (HLA) identical sibling hematopoietic cell donor, unless recommendation for enrollment is provided by the Comite de Surveillance following a review of the case.
• Clinically significant, active bacterial, viral, fungal, or parasitic infection.
• Contraindication to anesthesia for bone marrow harvesting.
• Any prior or current malignancy, myeloproliferative or immunodeficiency disorder.
• A white blood cell (WBC) count 3× upper limit of normal.
• This observation will not be exclusionary if a liver biopsy shows no evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis.
• Histopathological evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis on liver biopsy.
• Heart disease, with a left ventricular ejection fraction <25%.
• Kidney disease with a calculated creatinine clearance <30% normal value.
• Severe iron overload, which in the opinion of the physician is grounds for exclusion.
• A cardiac T2* <10 ms by magnetic resonance imaging (MRI).
• Evidence of clinically significant pulmonary hypertension requiring medical intervention.