A Treatment For Hemoglobinopathies via Fetal Globin Reactivation in Hematopoietic Stem Cells

Funding Type: 
Strategic Partnership I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Sickle cell disease (SCD) is an autosomal recessive disease in which a mutation in the beta globin gene results in the sickling of red blood cells. Affected individuals are predisposed to infection, and may present with pain crises, acute chest syndrome, and stroke. Pediatric patients with sickle cell disease (SCD) receive daily hydroxyurea, which controls disease by activating the gamma globin gene (shut down in infancy), thus reducing adverse effects of mutant beta globin. The clinical benefit of this has been shown by the reduction in the incidence of pain or acute chest syndrome, and a reduction in the need for blood transfusions. However, the effects of hydroxyurea are palliative and chronic therapy has been reported to be carcinogenic in isolated cases. Furthermore, most adults will become refractory to hydroxyurea treatment.

Contemporaneous with the development of hydroxyurea, other investigators have been exploring the potential of curing SCD with hematopoietic stem cell (HSC) transplantation. To date, approximately 400 patients have undergone allogeneic HSC transplantation following myeloablative conditioning. However, it is estimated that HLA-compatible HSC transplants are available to less than 20% of affected individuals and long term toxicities are substantial. The latter includes the need for chronic immunosuppression and the development of graft versus host disease (GVHD).

The proposed therapeutic intervention aims to provide a widely available functional cure for SCD and beta-thalassemia. During infancy, gamma-globin-containing fetal hemoglobin protects SCD and beta-thalassemia patients from developing disease symptoms until gamma globin is replaced by adult-type beta globin chains. The proposed approach combines the benefits of activating the gamma globin gene with the curative potential of HSC transplantation while abrogating the toxicities associated with hydroxyurea, chronic immunosuppression and GVHD. We hypothesize that harvesting HSCs from a patient with SCD or beta-thalassemia, using genome editing to permanently activate the gamma globin gene, and returning these edited HSCs to the patient could provide a lifetime of relief from SCD and beta-thalassemia symptoms. The use of a patient’s own cells is anticipated to be safer since the conditioning regimen would be nonmyeloablative, there is no need for chronic immunosuppression, and there would be no risk of GVHD. Importantly, this approach addresses all patients with SCD/beta-thalassemia with one treatment.

Statement of Benefit to California: 

Our treatment for hemoglobinopathies will benefit the approximately 5,000 SCD patients in the State of California by providing them with a better treatment option for this severe disease with significant unmet medical need (1). SCD is an ongoing health concern in California, with the California Newborn Screening Program detecting approximately 125 cases of SCD each year (2) . In addition to benefitting patients, our proposed curative treatment will also benefit California’s State Medicaid Program, Medi-Cal, through significant cost savings. Acute and chronic clinical manifestations of SCD (vaso-occlusive crisis, acute chest syndrome, stroke, etc.) lead to significant healthcare utilization, especially of the emergency department (ED). The majority of SCD Californians visit an ED more than once during the year; ED visits often result in hospital admission lasting 5-6 days on average for SCD patients. Of importance to the State of California, SCD patients are heavily reliant on Medicaid (~46%). The total lifetime health care costs for an average sickle cell patient are approximately $1 million (3). This translates to approximately $2.5 billion in total costs for the ~50% of SCD Californians covered by Medi-Cal. Thus, our proposed treatment has the potential to provide Medi-Cal significant savings by reducing the number of expensive inpatient hospitalizations and Emergency Department visits by SCD Californians.

1. J. A. Wolfson, S. M. Schrager, T. D. Coates, M. D. Kipke, Sickle-cell disease in California: a population-based description of emergency department utilization. Pediatr Blood Cancer 56, 413 (Mar, 2011).
2. California Department of Public Health: California Newborn Screening Program. http://www.cdph.ca.gov/programs/nbs/Pages/NBSSCDProviders.aspx -- accessed on 6/25/2012.
3. S. K. Ballas, The cost of health care for patients with sickle cell disease. Am J Hematol 84, 320 (Jun, 2009).