Customizing the genome as therapy for the β-hemoglobinopathies

Abstract

Despite nearly complete understanding of the genetics of the β-hemoglobinopathies for several decades, definitive treatment options have lagged behind. Recent developments in technologies for facile manipulation of the genome (zinc finger nucleases, transcription activator-like effector nucleases, or clustered regularly interspaced short palindromic repeats–based nucleases) raise prospects for their clinical application. The use of genome-editing technologies in autologous CD34+ hematopoietic stem and progenitor cells represents a promising therapeutic avenue for the β-globin disorders. Genetic correction strategies relying on the homology-directed repair pathway may repair genetic defects, whereas genetic disruption strategies relying on the nonhomologous end joining pathway may induce compensatory fetal hemoglobin expression. Harnessing the power of genome editing may usher in a second-generation form of gene therapy for the β-globin disorders.

Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation

“…42 Strategies that explore the use of mismatched related donors are ongoing 43,44 as are studies of gene therapy and gene editing, all of which are aimed at improving survival for SCD. [45][46][47] Transplantation of grafts from HLA-identical siblings offers excellent 5-year survival, and our results confirm this is an accepted treatment of severe SCD worldwide. Nevertheless, it is also important to study the effects of transplantation in the long term and to develop prospective trials of comparable patient cohorts to determine the relative merits of transplantation vs supportive care, especially in older patients with severe SCD.…”

Directed Evolution of Adenine Base Editors with Increased Activity and Therapeutic Application

“…At least 20% of HbF-expressing cells is hypothesized to be required to ameliorate symptoms of sickle cell disease and likely slightly higher levels of HbF are needed for -thalassemia. 25,26 Encouragingly, theglobin levels observed following ABE8 editing are consistent with HbF levels higher than these thresholds and greater than levels achieved with ABE7.10.…”

Treating sickle cell disease by targeting HbS polymerization

“…[10][11][12] Although these are potential therapies for patients in the United States, neither will be available for several decades for millions of patients in sub-Saharan Africa and elsewhere. 13 Therefore, what is needed to treat the vast majority of patients is an affordable drug that can be taken orally.…”