Improved lentivector-modified hematopoietic stem cell transplantation in the Townes mouse model of sickle cell disease.

Abstract

BACKGROUND AIMS: Sickle cell disease (SCD) affects about 100 000 Americans with higher prevalence in minorities such as African and Hispanic Americans. Despite current standards of care, patients with SCD have a lower quality of life and 20 years shorter life expectancy compared to the general population. Curative approaches like allogeneic hematopoietic stem cell transplant (HSCT) have limited applications due to lack of compatible donors, risk for graft versus host disease, graft rejection, and the high fitness requirements for the patients. The Townes SCD mice are useful for evaluation of gene therapies in the preclinical setting; they recapitulate human SCD, displaying severe anemia, end-organ damage, and early mortality. METHODS: We tested a gene therapy using a lentiviral (LV) vector harboring a human β-globin transgene with three antisickling mutations. It was delivered via transduction of bone marrow cells from syngeneic Townes mice homozygous for sickle hemoglobin (SS) and transplanted into SS recipients. We optimized this transplant method using an increased LV dose, an increased cell dose per recipient, and post-transplant blood transfusions. We evaluated the recipients using functional assays to gauge recovery and gene therapy efficacy. RESULTS: Compared to nontreated mice, we observed improved hemoglobin and hematocrit counts, reduced RBC sickling, and betterment of disease-related pathologies in the heart, lung, spleen, and kidney. CONCLUSIONS: This specific approach serves as a basis for future preclinical testing of gene therapies in SCD.