Bluebird bio has developed two prominent gene therapies with distinct mechanisms of action:

1. Elivaldogene autotemcel (SKYSONA): This gene therapy targets cerebral adrenoleukodystrophy (CALD), a rare genetic disorder affecting the nervous system and adrenal glands. CALD is caused by mutations in the ABCD1 gene, leading to the accumulation of very long-chain fatty acids (VLCFAs) in the brain and adrenal glands. Eli-cel works by introducing a functional copy of the ABCD1 gene into a patient's own hematopoietic stem cells (HSCs). These modified HSCs are then infused back into the patient, where they engraft in the bone marrow and begin producing functional ALD protein. This protein helps break down VLCFAs, preventing their harmful buildup and halting disease progression. Specifically, eli-cel uses a lentiviral vector to deliver the ABCD1 gene into the patient's HSCs. This vector integrates the gene into the cell's DNA, allowing for long-term expression of the ALD protein.

2. Lovotibeglogene autotemcel (LentiGlobin for sickle cell disease): This gene therapy addresses sickle cell disease (SCD), a genetic blood disorder characterized by abnormal hemoglobin (HbS). HbS causes red blood cells to become rigid and sickle-shaped, leading to vaso-occlusive crises, hemolysis, and other complications. LentiGlobin works by adding a modified β-globin gene into a patient's HSCs. This modified gene produces an anti-sickling hemoglobin called HbA, which counteracts the effects of HbS. The modified HSCs are then reintroduced into the patient, where they produce red blood cells containing HbA, reducing sickling and improving blood flow. LentiGlobin also utilizes a lentiviral vector (BB305) to deliver the modified β-globin gene into the patient's HSCs. The increased production of HbA leads to a reduction in hemolysis (destruction of red blood cells) and a resolution of severe vaso-occlusive events.

In summary, both therapies involve ex vivo gene modification of a patient's own HSCs using lentiviral vectors. Eli-cel provides a functional copy of a missing gene (ABCD1) to correct the underlying genetic defect in CALD, while LentiGlobin adds a modified gene to produce an anti-sickling hemoglobin (HbA) in SCD, counteracting the effects of the disease-causing HbS.

Bluebird bio has developed or is developing gene therapies for the following indications:

• Cerebral adrenoleukodystrophy (CALD): Elivaldogene autotemcel (Skysona, Lenti-D) is an approved gene therapy for early CALD in patients under 18 years old with an ABCD1 genetic mutation and no HLA-matched sibling HSC donor.
• Sickle cell disease (SCD): LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) is a gene therapy involving autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector. This vector encodes a modified β-globin gene, producing an antisickling hemoglobin, HbA. While showing promise, the trial was temporarily suspended due to cases of AML/MDS in participants, raising concerns about potential causes such as busulfan or insertional mutagenesis. The therapy has resumed with a modified approach.
• β-thalassemia: LentiGlobin BB305 vector gene therapy and Betibeglogene autotemcel (beti-cel) are being investigated for transfusion-dependent β-thalassemia. These therapies involve transducing autologous CD34+ cells with a vector encoding a modified β-globin gene (HbA T87Q) and reinfusing them after myeloablative conditioning. Studies have shown these therapies can reduce or eliminate the need for long-term red-cell transfusions.

It's important to note that the development and approval status of these therapies can change, and it's always best to consult the latest medical information for the most up-to-date details.