Gene therapy treats diseases at their genetic root by introducing functional copies of a gene into a person’s cells. Bluebird bio is a leader in this area, developing gene therapies for severe genetic disorders.
Understanding Bluebird Gene Therapy
Bluebird bio’s gene therapy uses ex vivo gene addition, where a patient’s cells are modified outside the body. This process involves collecting a patient’s own blood stem cells, which are sent to a manufacturing facility. There, functional gene copies are introduced into these cells using a lentiviral vector (LVV). Lentiviral vectors are modified viruses designed to insert genetic material into the original cell’s DNA, ensuring subsequent cells also carry the functional gene.
Once modified, these cells are expanded in a laboratory before being returned to the patient. This ex vivo method allows for precise control over genetic modification and reduces immune rejection risk, as the patient receives their own altered cells. Bluebird bio customizes each gene therapy. While the therapy is a single treatment, the entire process, from cell collection to re-infusion and recovery, can span several months.
Diseases Targeted by Bluebird Gene Therapy
Bluebird bio’s gene therapies target specific genetic disorders.
Transfusion-Dependent Beta-Thalassemia (TDT)
TDT is a rare genetic blood disease caused by mutations in the beta-globin gene, leading to reduced or absent adult hemoglobin. Zynteglo (betibeglogene autotemcel) adds functional copies of a modified beta-globin gene into a patient’s blood stem cells. This enables them to produce functional adult hemoglobin, potentially eliminating the need for regular red blood cell transfusions, which are often required every two to five weeks.
Cerebral Adrenoleukodystrophy (CALD)
CALD is a rare, progressive neurodegenerative disease primarily affecting young boys. It is caused by mutations in the ABCD1 gene, resulting in the accumulation of very long-chain fatty acids in the brain and spinal cord, leading to neurological decline. Skysona (elivaldogene autotemcel) adds functional copies of the ABCD1 gene into a patient’s hematopoietic stem cells. This allows for the production of the ALD protein, which helps break down these fatty acids and may slow or prevent inflammation and demyelination. This therapy is for boys aged 4 to 17 with early, active CALD who lack a suitable matched donor for a stem cell transplant.
Sickle Cell Disease (SCD)
SCD is a lifelong condition characterized by deformed red blood cells that can cause blockages in blood vessels, leading to pain and complications. Lyfgenia (lovotibeglogene autotemcel) is approved for patients 12 years and older with SCD who have a history of vaso-occlusive events (VOEs). This therapy adds a functional beta-globin gene to the patient’s blood stem cells, enabling the production of an anti-sickling adult hemoglobin (HbAT87Q), which can reduce or eliminate VOEs.
The Process of Bluebird Gene Therapy
Patients undergoing bluebird gene therapy follow a multi-step process.
Consultation and Evaluation
The journey begins with a consultation at a Qualified Treatment Center. If gene therapy is an option after initial evaluations, cell collection begins.
Cell Collection and Modification
Medications are administered to help the patient’s blood stem cells move from the bone marrow into the bloodstream (mobilization). Following mobilization, apheresis collects these stem cells from a vein, typically taking several hours. The collected stem cells are then transported to a manufacturing facility where they are modified with the functional gene. This manufacturing and testing phase can take approximately 70-90 days before the gene therapy product is ready.
Conditioning and Infusion
Before the gene therapy infusion, patients receive chemotherapy for several days to clear existing bone marrow for the new modified cells. This conditioning is performed while the patient is hospitalized. Once conditioning is complete, the gene therapy is administered as a one-time intravenous infusion, typically taking 30 minutes or less per bag. Patients remain hospitalized for several weeks post-infusion to monitor recovery and ensure the modified cells engraft and begin producing new blood cells.
Effectiveness and Safety Considerations
Zynteglo for Beta-Thalassemia
Clinical trials for Zynteglo have shown effectiveness, with about 9 out of 10 (89%) evaluable patients achieving transfusion independence. They no longer required regular red blood cell transfusions and maintained a median total hemoglobin level of 11.5 g/dL. Long-term follow-up for Zynteglo extends beyond 10 years for some patients, showing sustained transfusion independence and normal or near-normal hemoglobin levels. Common side effects include mucositis, febrile neutropenia, vomiting, and fever. Delayed platelet engraftment has been observed, increasing bleeding risk until platelet recovery. Patients are monitored for potential hematologic malignancies for at least 15 years after treatment, though no cases of blood cancer directly linked to Zynteglo have been reported.
Skysona for Cerebral Adrenoleukodystrophy
Skysona has demonstrated efficacy in slowing neurologic dysfunction. Data showed that 30 out of 32 patients had stable neurological function scores, and 26 experienced no major functional disabilities at the most recent evaluation. Skysona carries a boxed warning for hematologic malignancies, as some patients have developed blood cancers, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), between 14 and 92 months post-treatment. These cases have been linked to clonal vector insertions in cancer genes. Patients are monitored for these risks with complete blood counts and integration site analysis for at least 15 years.
Lyfgenia for Sickle Cell Disease
Lyfgenia has shown sustained benefits, with data from 58 patients showing durable production of anti-sickling adult hemoglobin exceeding 40% and stable total hemoglobin levels without transfusions. This therapy has led to the elimination or reduction of vaso-occlusive events in all patients in some studies, with follow-up extending up to five years. In a separate analysis, 27 patients with a history of overt or silent stroke experienced no stroke recurrence through nine years of follow-up. Common side effects include stomatitis, thrombocytopenia, neutropenia, and febrile neutropenia. While two patients in earlier trials died from acute myeloid leukemia, these cases were associated with an earlier version of the therapy and different manufacturing processes. Patients receiving Lyfgenia are monitored for hematologic malignancies with complete blood counts at least every six months for 15 years.