Refining A New Gene Therapy for Sickle Cell Disease 

Gene therapy for people with severe sickle cell disease (SCD) has been designed to insert an engineered beta-globin gene into patients’ stem cells to increase levels of therapeutic hemoglobin. Now in a phase 1 clinical trial (NCT02140554), the therapeutic hemoglobin is designed to counterbalance the defective hemoglobin that does a poor job of carrying oxygen and causes intravascular sickling, resulting in organ injury and pain. 

In SCD, abnormal hemoglobin causes red blood cells to become sickle-shaped and to break down faster than normal, resulting in poor delivery of oxygen throughout the body. As a result, people with SCD experience acute episodes of pain known as sickle cell or vaso- occlusive crisis and multi-system organ damage. Gene therapy is designed to prevent vaso-occlusive crisis by inserting a gene to produce “normal” hemoglobin, which would improve the shape and oxygen-carrying ability of red blood cells. Stem cells are collected from a patient via apheresis and then transduced with a virus that carries a gene for the therapeutic hemoglobin protein, called T87Q. The transduced stem cells, which are given back to the patient through an infusion, produce red blood cells that carry hemoglobin T87Q. 

Refinements to the process of stem cell collection and transduction have increased production of hemoglobin T87Q, bringing people with SCD closer to a cure, according to pediatric hematologist Julie Kanter, M.D., who leads the clinical trial at MUSC. “The interim results indicate significant improvement in transduction and therapeutic globin production, demonstrating the potential for curative intent,” says Kanter. 

In the first group of patients, stem cells were collected through multiple bone marrow harvests. For the second group
of patients, the protocol changed to use a new process called plerixafor mobilization with apheresis, which helps release stem cells into the bloodstream, allowing them to be collected through a blood draw.

The method greatly improved the number and quality of stem cells collected. Then Bluebird Bio, Inc., which makes the therapeutic globin protein, used an improved proprietary transduction process to increase the number of stem cells that were transduced with the gene for T87Q. 

In patients who underwent the unrefined therapy, hemoglobin T87Q constitutes about 13 percent of their total hemoglobin. In contrast, in patients who were treated with the refined therapy, T87Q makes up between 29 and 62 percent of their total hemoglobin. Most importantly, levels of abnormal hemoglobin have dropped in these patients, indicating that the therapeutic hemoglobin protein is indeed compensating. 

The trial is currently in phase 2 trials at multiple sites. The researchers plan to begin phase 3 in one to two years, which will bring the gene therapy to a larger number of people with SCD. 

--SVER AUNE
Source: Progressnotes Fall 2018