Antoniani, C et al, 2018, Blood
Link to abstract
Synthesis of fetal gamma-globin is usually silenced to a large degree after the first months of life. Upregulation of gamma-globin production was shown to mitigate the severity of beta-globin diseases like beta-thalassemia and sickle cell disease. This report investigated whether upregulation of fetal hemoglobin through genome editing might be beneficial in beta-globin diseases.
Large deletions in the beta-globin gene lead to hereditary persistence of fetal hemoglobin. Mutations in these locations were introduced with a CRISPR/Cas9 system in apheresed blood progenitor cells of patients with sickle cell disease or beta-thalassemia.
Of different deletions tested, a 13.6kb measuring deletion (largest) was the most effective with robust fetal hemoglobin production. The same was true for an inversion that spanned the same region. Half the edited cells and about 1/3 overall carried the biallelic rearrangement.
So far, this is a cell line experiment and results cannot directly be transferred to humans. It remains to be proven that these genetically modified cells do engraft in a recipient with sickle cell disease or thalassemia.
This is a promising new approach on how to treat beta-globin diseases with gene editing of patient-derived cells to increase hemoglobin F production. A clinical trial utilizing this approach is in the works and has already passed several regulatory hurdles.