Table 1.
Summary of PCSK9 genome editing in rhesus macaques after systemic AAV vector administration
| Animal No. | Sex | Age at dosing (years) | Endonuclease | AAV serotype | Other treatment | Vector dose (GC/kg) | Levels in steady phasea % of day-0 level (absolute level) |
Editing in the third liver biopsy/necropsy |
|||
|---|---|---|---|---|---|---|---|---|---|---|---|
| PCSK9 (ng/mL) | LDL (mg/dL) | Time | On-target indel %b | Time point | |||||||
| RA1866 | M | 4.9 | M1PCSK9 | AAV8 | 3.0E+13 | 15.5 ± 0.5 (17.9 ± 0.5) | 43.8 ± 1.6 (25.4 ± 0.9) | day 56–1237 (n = 55) | 64.4 | d1070 | |
| RA1857 | M | 4.9 | M1PCSK9 | AAV8 | 6.0E+12 | 54.9 ± 1.8 (36.8 ± 1.2) | 60.1 ± 1.3 (28.8 ± 0.6) | day 56–1237 (n = 55) | 44.4 | d1070 | |
| RA1829 | F | 5.1 | M1PCSK9 | AAV8 | 2.0E+12 | 74.8 ± 2.8 (195.3 ± 7.1) | 67.2 ± 1.2 (49.8 ± 0.9) | day 56–1134 (n = 50) | 24.0 | d989 | |
| RA2334 | M | 4.0 | M1PCSK9 | AAV8 | 2.0E+12 | 83.2 ± 2.9 (193.0 ± 6.6) | 77.4 ± 1.5 (57.8 ± 1.2) | day 56–1134 (n = 50) | 9.5 | d989 | |
| RA2125 | F | 4.2 | M2PCSK9 | AAV8 | 6.0E+12 | 37.5 ± 1.9 (65.5 ± 3.4) | 61.2 ± 2.0 (23.9 ± 0.8) | day 56–280 (n = 16) | 38.8 | d284 (necropsy) | |
| RA2343 | M | 3.9 | M2PCSK9 | AAV8 | 6.0E+12 | 43.7 ± 1.5 (98.7 ± 3.4) | 60.4 ± 1.3 (46.5 ± 1.0) | day 56–1142 (n = 50) | 41.8 | d995 | |
| RA3167 | M | 4.7 | M2PCSK9 | AAV8 | prednisolone (d0-d76) | 6.0E+12 | 77.5 ± 5.0 (103.7 ± 6.7) | 85.7 ± 2.1 (49.7 ± 1.2) | day 56–789 (n = 39) | 19.2 | d642 |
| RA3169 | M | 4.0 | M2PCSK9 | AAV8 | prednisolone (d0-d76) | 6.0E+12 | 20.2 ± 1.2 (36.8 ± 2.1) | 44.4 ± 1.7 (31.1 ± 1.2) | day 56–789 (n = 39) | 57.2 | d642 |
| RA2083 | F | 5.8 | M2PCSK9 | AAV3B | 6.0E+12 | 26.9 ± 1.3 (98.0 ± 4.9) | 57.0 ± 1.7 (37.6 ± 1.1) | day 56–699 (n = 35) | 30.3 | d531 | |
| RA2396 | F | 5.1 | M2PCSK9 | AAV3B | 6.0E+12 | 51.1 ± 2.5 (150.3 ± 7.2) | 61.3 ± 1.8 (74.8 ± 2.2) | day 56–699 (n = 36) | 23.4 | d531 | |
AAV, adeno-associated virus; GC, genome copy; LDL, low-density lipoprotein.
Steady phase is arbitrarily defined as day 56 post vector administration to the most current time point for each animal or to the final time point for RA2125, and the number of time points for LDL is shown in parentheses. Data are presented as the percentage of the day-0 level, and absolute levels are shown in parentheses. The means ± SEM are shown. The reduction compared with pretreatment is significant (p < 0.001) based on a one-sided one-sample t test.
On-target indel % in hepatocytes is based on mean AMP-seq on third biopsy or necropsy (RA2125) samples (Figure 2A) and adjusted 1.4-fold to reflect the indel % in hepatocytes, which represent ~70% of total liver cells.