TABLE 2.
Experimental studies of base editing for RH.
| Species | References | Target | Cas nuclease | Model | Delivery |
|---|---|---|---|---|---|
| Mouse | Chadwick et al. (2017) | Pcsk9 (Trp-159 site) | BE3 | 5-week-old male C57BL/6J mice | Adenoviral vector |
| Carreras et al. (2019) | mouse Pcsk9 and human PCSK9 | BE3 | 10-week-old male hPCSK9-KI mice and wildtype mice | Adenoviral vector | |
| Chadwick et al. (2018) | Angplt3 (Gln-135 site) | BE3 | 5-week-old male C57BL/6J mice | Adenoviral vector | |
| Angplt3+Pcsk9 | BE3 | 5-week-old male C57BL/6J mice | Adenoviral vector | ||
| Angplt3 | BE3 | 5-week-old male B6.129S7-Ldlrtm1Her/J mice | Adenoviral vector | ||
| Rothgangl et al. (2021) | PCSK9 | ABEmax | mice | Lipid nanoparticle | |
| Macaque | Musunuru et al. (2021) | PCSK9 | ABE8.8-m | cynomolgus monkeys | Lipid nanoparticle |
| Rothgangl et al. (2021) | PCSK9 | ABEmax | cynomolgus macaques (Macaca fascicularis) | Lipid nanoparticle |
| Species | References | Editing rate | Decreased levels of target protein | Degree of plasma cholesterol decrease |
|---|---|---|---|---|
| Mouse | Chadwick et al. (2017) | Day 5: a median rate of 25% (average rate of 24%, max = 34%); Week 4: median rate of 28% | Day 5: PCSK9 protein (∼56%); Week 4: PCSK9 protein (∼54%) | Day 5: cholesterol (28%); Week 4: cholesterol (28%) |
| Carreras et al. (2019) | most in the human PCSK9 and mouse Pcsk9 were the targeted C to T transitions | Week 3: human PCSK9 protein (∼32%); mouse PCSK9 protein (∼28%) | significant reductions in total cholesterol | |
| Chadwick et al. (2018) | Day 7: a median editing rate of 35% | Day 7: mean levels of plasma ANGPTL3 protein (49%) | Day 7: triglycerides (31%); cholesterol (19%) | |
| - | Day 7: ANGPTL3 protein (∼48%); PCSK9 protein (∼57%) | Day 7: triglycerides (∼27%); cholesterol (∼29%) | ||
| - | Day 14: ANGPTL3 protein (∼24%) | Day 14: triglycerides (56%); cholesterol (51%) | ||
| Rothgangl et al. (2021) | 67% | ∼95% | LDL-C 58% | |
| Macaque | Musunuru et al. (2021) | almost complete editing of PCSK9 | nearly 90% | LDL-C up to 60% |
| Rothgangl et al. (2021) | 34% | 32% | LDL-C 14% |
PCSK9, proprotein convertase subtilisin-kexin type 9; ANGPTL3, angiopoietin-like protein 3; BE3, third-generation base editor; ABE, adenine base-editor.