bluebird bio’s three distinct investigational gene therapies utilize gene addition combined with an autologous hematopoietic stem cell transplant (HSCT). This process works by using a patient’s own blood – or hematopoietic – stem cells. These cells are very important, as they have the potential to develop into other types of blood cells. Autologous HSCT, which is when a patient receives a transplant using their own stem cells has several benefits over traditional stem cell transplants. First, there is no need to identify a matched donor, which can be very challenging as only 30% of patients have a genetically matched sibling donor. Additionally, using a patient’s own stem cells eliminates the risk of graft rejection, which can occur with traditional allogeneic transplants when a recipient’s immune system recognizes a donor’s cells as foreign, although risks commonly associated with mobilization and conditioning still apply.

Gene addition treats diseases at the genetic level by adding genetic material to a person’s cells to compensate for a missing or faulty gene. In gene addition therapy, a functional gene is introduced into cells either ex vivo – where the cells are modified outside the body and then transplanted back in, or in vivo – where the cells are modified inside the body. bluebird bio’s gene therapies are introduced ex vivo.

There are many different approaches to ex vivo gene therapy, but the administration process to deliver those different therapies is the same across many modalities. Importantly, gene therapies are often referred to as “one-time treatments” – but while the therapy itself is administered only once, the treatment process from start to finish is complex and has several steps that can take several months.

Here’s how it works.

Mobilization and apheresis

As a first step, medications are given to help the blood stem cells leave the bone marrow and enter the blood stream – this is known as mobilization. In the next step the blood stem cells are collected from a vein through a process called apheresis, which typically occurs on or around fifth day of mobilization and takes several hours. In apheresis, the part of the blood containing stem cells is separated from the rest of the blood, which is returned back to the body. This process typically takes place at a specialized treatment center.

Manufacturing

The collected stem cells are shipped from the apheresis collection center to the drug product manufacturing facility, where they are processed and purified, and then used to create the gene therapy.

To create the gene-modified cells needed for gene therapy, copies of the functional gene are added to the blood stem cells.

To get the functional gene inside the cells, a delivery system that carries a copy of the functional gene is created. The delivery system is called a vector. bluebird bio uses lentiviral vectors, which have the ability to insert genetic material into stem cells. In this way, the functional gene becomes part of the original cell’s DNA and every new cell that arises from it.

Viral vectors are built using a blueprint of a virus—not the actual virus itself. Only the parts of the blueprint of the virus that help with delivering genetic material are used.

The gene therapy drug product is tested for purity and potency using validated assays. Quality control occurs throughout the manufacturing process to ensure that the final gene therapy product meets high standards of purity and potency. The product must meet release criteria prior to the patient undergoing the conditioning regimen to prepare for infusion.

Conditioning

Before the gene therapy can be infused into the patient, the existing bone marrow and blood stem cells are cleared out to make room for the new cells with the functional gene. This process is known as conditioning, and is performed in the days prior to gene therapy infusion while hospitalized at a specialized treatment center. The entire conditioning process takes six days.

Risks commonly associated with chemotherapy include fatigue, gastrointestinal side effects such as nausea and vomiting, and infections.

Infusion

On the day of infusion, the gene therapy drug product is thawed and administered intravenously, like a blood transfusion. This takes place at the bedside at a specialized treatment center. The process may require multiple bags of cells and takes several hours.

Engraftment

Once the gene therapy has been infused, the goal is that the cells with the functional gene will start to move into the bone marrow. Over time, the transplanted cells settle in the bone marrow, where they start to grow and produce new blood cells with the functional gene. This process is called engraftment. The timing of engraftment usually takes several weeks. Patients remain in the hospital for several weeks of monitoring.

Discharge and monitoring

Regular long-term monitoring after gene therapy allows researchers to identify potential risks and to assess the impact of the therapy. Patients also have the option of participating in long-term follow-up studies in order to learn as much as possible about these new therapies.

The nature of follow-up care will depend on many factors, but patients will most likely need to return to the treatment center for outpatient visits in the weeks and months following discharge. Patients should follow their healthcare provider's instructions on the frequency of follow-up monitoring.