Table 2.
Design of the 3-month NHP GLP toxicology study to evaluate safety and determine the BD of AAV5-hGRK1-GUCY2D
| Groupa,b | No. of females | Systemic steroid (through dosing phase interval)c | Dosing regimen |
Dose level (vg/eye)d |
Dose concentration (vg/mL) |
|||
|---|---|---|---|---|---|---|---|---|
| Left eye | Right eye | Left eye | Right eye | Left eye | Right eye | |||
| 1 (control) | 3 | week 6 | not dosed | vehicle | N/A | 0 | N/A | 0 |
| 2 | 3 | week 6 | not dosed | test article | N/A | 1.5 × 1010 | N/A | 1.0 × 1011 |
| 3 | 3 | week 6 | not dosed | test article | N/A | 5.0 × 1010 | N/A | 3.3 × 1011 |
| 4 | 3 | week 6 | not dosed | test article | N/A | 1.5 × 1011 | N/A | 1.0 × 1012 |
| 5 (control) | 3 | day 3 | not dosed | vehicle | N/A | 0 | N/A | 0 |
| 6 | 3 | day 3 | not dosed | test article | N/A | 1.5 × 1010 | N/A | 1.0 × 1011 |
| 7 | 3 | day 3 | not dosed | test article | N/A | 5.0 × 1010 | N/A | 3.3 × 1011 |
| 8 | 3 | day 3 | not dosed | test article | N/A | 1.5 × 1011 | N/A | 1.0 × 1012 |
N/A, not applicable.
Female cynomolgus monkeys (M. fascicularis) were assigned to eight groups, and doses were administered as indicated. Animals were dosed once on day 1 of the dosing phase via subretinal injection into the right eye at a volume of 150 μL/right eye. The vehicle control article/diluent was Alcon BSS with 0.014% polysorbate 20. Assessment of toxicity was based on mortality, clinical observations, body weight, body weight change, food consumption, ophthalmic observations, intraocular pressure (IOP), optical coherence tomography (OCT), color fundus photography, full-field and multifocal electroretinography (ffERG and mfERG, respectively), and clinical and anatomical pathology. Blood and aqueous humor samples were collected for immunogenicity analysis.
Groups 1 and 5 received the vehicle control article only.
Animals in all groups (1–8) received subconjunctival dexamethasone (DEX; 2 mg) on day 1 as a routine component of the subretinal procedure, with DEX administered after test article injection.
Animals in groups 1–4 were administered systemic prednisolone (via oral administration) beginning 3 days prior to dosing and continuing through week 6 of the dosing phase in addition to the standard topical DEX as part of the medication regimen. Animals in groups 5–8 were administered systemic prednisolone (via oral administration) beginning 1 day prior to dosing and continuing through day 3 of the dosing phase in addition to the standard topical DEX as part of the medication regimen.
Dose levels were based on the test article as supplied. The right eye of each animal was dosed at a volume of 150 μL.