Potential targets for therapeutic genome editing for the β-globin disorders
| Target . | Repair strategy . | Efficiency . | Advantages/Disadvantages . |
|---|---|---|---|
| Repair of SCD allele | HDR | Low-moderate | Single target allele; inadvertent generation of β-thalassemia alleles |
| Repair of β-thalassemia allele | HDR | Low-moderate | Heterogeneous target alleles |
| Recreation of nondeletional HPFH | HDR | Low-moderate | Inadvertent generation of γ-null alleles; identified HPFH patients support mutation tolerance/clinical benefit |
| Recreation of deletional HPFH | NHEJ | Low-moderate | Insufficient efficiency of targeted deletion; identified HPFH patients support mutation tolerance/clinical benefit |
| Other targets in β-globin cluster | NHEJ | — | Targets unknown |
| BCL11A | NHEJ | High | HSC/B-cell dysfunction due to BCL11A requirement; haploinsufficient patients have significant HbF induction |
| BCL11A enhancer | NHEJ | High | Erythroid-specific BCL11A loss; haploinsufficient patients have significant HbF induction |
| α-Globin | NHEJ | Moderate-high | Balance α-β chains; inadvertent generation of α-thalassemia cells |
| KLF1 | NHEJ | High | Broad role in cell proliferation and cellular development |
| MYB | NHEJ | High | Broad role in cell proliferation and cellular development |
| LRF/ZBTB7A | NHEJ | High | Broad role in cell proliferation and cellular development |
| EHMT1/EHMT2 | NHEJ | High | Role in hematopoiesis unknown |
| LIN28B pathway | NHEJ | High | Role in hematopoiesis unknown |
| Target . | Repair strategy . | Efficiency . | Advantages/Disadvantages . |
|---|---|---|---|
| Repair of SCD allele | HDR | Low-moderate | Single target allele; inadvertent generation of β-thalassemia alleles |
| Repair of β-thalassemia allele | HDR | Low-moderate | Heterogeneous target alleles |
| Recreation of nondeletional HPFH | HDR | Low-moderate | Inadvertent generation of γ-null alleles; identified HPFH patients support mutation tolerance/clinical benefit |
| Recreation of deletional HPFH | NHEJ | Low-moderate | Insufficient efficiency of targeted deletion; identified HPFH patients support mutation tolerance/clinical benefit |
| Other targets in β-globin cluster | NHEJ | — | Targets unknown |
| BCL11A | NHEJ | High | HSC/B-cell dysfunction due to BCL11A requirement; haploinsufficient patients have significant HbF induction |
| BCL11A enhancer | NHEJ | High | Erythroid-specific BCL11A loss; haploinsufficient patients have significant HbF induction |
| α-Globin | NHEJ | Moderate-high | Balance α-β chains; inadvertent generation of α-thalassemia cells |
| KLF1 | NHEJ | High | Broad role in cell proliferation and cellular development |
| MYB | NHEJ | High | Broad role in cell proliferation and cellular development |
| LRF/ZBTB7A | NHEJ | High | Broad role in cell proliferation and cellular development |
| EHMT1/EHMT2 | NHEJ | High | Role in hematopoiesis unknown |
| LIN28B pathway | NHEJ | High | Role in hematopoiesis unknown |