Despite the fact that over 275000 infants are born with sickle cell disease every year, there is no universal pharmacologic treatment for the disease. Sickle cell disease is caused by a single typo in the body’s blueprint for a gene called hemoglobin, the molecule used by red blood cells to carry oxygen through the body. Because repairing this typo can effectively cure sickle cell disease, researchers have developed several gene therapy based treatments to replace the defective gene with a healthy version. A recent study published in the New England Journal of Medicine describes the successful results of a patient who received gene therapy for sickle cell and has experienced what seems to be a reversal of the disease.
Sickle cell disease is a serious condition caused by a single typo in the DNA alphabet of the gene for hemoglobin, which is the oxygen carrying material in red blood cells. The defective gene causes red blood cells to stiffen and adopt the characteristic crescent “sickle” shape (Pauling et al. 1949). Belying the simplicity of its cause, sickle cell disease results in multiple complex pathologies, leading to overall reduced life expectancy due to the reduced ability of red bloods cells to carry out their normal function and the extensive damage these misshapen cells inflict on microvasculature (Steinberg and Rodgers, 2001). Most notably, people with sickle cell disease suffer from frequent pain crises, known as vaso-occlusive episodes, which often result in hospitalization. The impact of pain and symptoms is perhaps most acute in quality of life measures; patients commonly report low self-esteem, feelings of hopelessness due to frequent hospital visits, and harm to their schooling and employment for children and adults, respectively.
For the more than 275,000 infants born with sickle cell disease every year, treatment options are limited (Ribeil et al. 2017). Hydroxyurea, the only FDA approved drug for sickle cell disease, is effective in approximately one-third of patients, despite its relatively high toxicity. Alternatively, patients can receive a bone marrow transplant, which infuses their body with cells from a healthy donor. Due to immunosuppressive therapies needed to avoid graft rejection, invasiveness of the procedure, and high cost, bone marrow transplant remains a treatment with limited effect on the worldwide burden of sickle cell disease.
Because sickle cell disease results from a single mutation, researchers have sought to use gene therapy as a novel one-time treatment that could potentially last a lifetime. Gene therapy replaces defective or missing genes with normal ones in order to “cure”, or reverse, diseases of genetic origin. Scientists at Bluebird Bio, based out of Cambridge, Massachusetts, appear to have harnessed engineered viruses to efficiently deliver a gene therapy cure for sickle cell patients. The treatment inserts the healthy hemoglobin gene (free of the genetic typo) into a patient’s own stem cells using a modified virus. Once the treated cells are introduced back into the patient’s body they develop into healthy red blood cells that produce normal hemoglobin. The power of this approach is that stem cells can remain in the patient for a lifetime, continually providing a source of healthy red blood cells.
In 2014, a 13-year-old sickle cell patient in Paris, France was treated with the new gene therapy approach. Fifteen months later, the boy is a healthy 15 year old who no longer suffers from recurrent pain episodes. Researchers found that at least half of his red blood cells now contain normal hemoglobin and are correctly shaped. While not fully eliminating sickle red blood cells from circulation, the current treatment has provided a therapeutic effect unparalleled by pharmaceutical interventions; the treated teen has in fact been able to discontinue all previous sickle cell medications. To date, six other patients with sickle cell disease have been similarly treated. Although unpublished and ongoing, studies on these patients suggest incremental improvements are needed for repeated positive results as were seen in the first French patient. Researchers are already working diligently to adjust their methods to achieve repeated positive therapeutic results in all patients (Ribeil et al. 2017).
In addition to sickle cell disease, gene therapy is currently being adapted for the treatment of a myriad of diseases where discrete genetic abnormalities have been identified. There are currently open trials for other diseases in which no universal treatments exist such as X-SCID (known as “bubble boy” disease), hemophilia, Alzheimer’s disease, Parkinson’s disease, and various cancers including pancreatic, lung, prostate, breast, and ovarian. As improvements in DNA sequencing and analysis allow researchers to discover genetic markers of disease, gene therapy offers hope to patients that new treatments will be developed in the near future.
Pauling, L., et al. (1949). “Sickle cell anemia a molecular disease.” Science 110(2865): 543-548.
Ribeil, J. A., et al. (2017). “Gene Therapy in a Patient with Sickle Cell Disease.” N Engl J Med 376(9): 848-855.
Steinberg, M. H. and G. P. Rodgers (2001). “Pathophysiology of sickle cell disease: role of cellular and genetic modifiers.” Semin Hematol 38(4): 299-306.