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Up-regulation of gamma-globin may benefit patients with beta-thalassemia, sickle cell disease
NEW ORLEANS — Zinc finger nucleases elevated gamma-globin levels, which may have therapeutic applications in patients with beta-thalassemia and sickle cell disease, according to research presented at the ASH Annual Meeting and Exposition.
“The hemoglobinopathies represent the most common genetic diseases on the planet, and the unmet medical need is severe,” Fyodor D. Urnov, PhD, of Sangamo BioSciences, told HemOnc Today. “Our work aims to develop an approach that uses genome editing of the patient’s own hematopoietic stem cells that would be broadly applicable to patients with both beta-thalassemia and sickle cell disease. For this reason, we focused on targeted genetic engineering of regulators of fetal globin gene expression.”
Fyodor D. Urnov
Urnov and colleagues at Sangamo, in collaboration with scientists at the University of Washington, evaluated zinc finger nucleases (ZFNs) that target regulators of gamma-globin gene transcription in human hematopoietic stem cells, including Bcl11a, Klf1 and specific positions in the gamma-globin promoters associated with fetal hemoglobin hereditary persistence.
Researchers treated CD34+ hematopoietic stem cells with these ZFNs and differentiated them into erythroid cells. They then observed potent elevation of gamma-globin messenger RNA (mRNA) and protein levels without significantly altering erythroid development.
Researchers observed a similar gamma-globin elevation in red blood cell progeny of genome-edited CD34+ cells from patients with sickle cell disease and beta-thalassemia.
A normalization of the beta-like to alpha-globin ratio was observed in red blood cells from two patients with beta-thalassemia major.
Researchers then used a clinical-grade electroporation device to deliver mRNA encoding ZFNs pairs to mobilized adult CD34+ cells at large scale (˃108 cells).
The ZFNs appeared highly specific and were well tolerated.
Engraftment of the modified cells lasted for longer than 16 weeks (about 25% human chimerism in mouse bone marrow) in transplantation experiments in immunodeficient mice.
Researchers confirmed elevation of gamma-globin following ex vivo erythroid differentiation of human precursor cells isolated from the bone marrow of transplanted animals.
“In a single stem, we obtained 80% single stem-targeted genome editing in human stem cells,” Urnov said during a press conference. “This is without precedent. Efficiencies of that scale of never been achieved in the history of biology.”
For more information:
Reik A. Abstract #434. Presented at: ASH Annual Meeting and Exhibition; Dec. 7-10; New Orleans.
Disclosure: Researchers report employment with Sangamo BioSciences.