Dose-Response Characteristics of Retinal Inactivation Due to Intravitreal Injections of Tetrodotoxin in Nonhuman Primates.

PURPOSE: Temporary retinal inactivation of the fellow eye with intravitreal tetrodotoxin (TTX) has shown promise as a treatment strategy for deprivation amblyopia in mouse and cat models. The purpose of this study was to evaluate the duration of retinal inactivation achieved with different doses of TTX in nonhuman primates (NHPs), while also assessing functional and structural measures of vision to determine the safety of this treatment approach.

METHODS

Three adult and four infant NHPs received varying doses of TTX (115-4800 ng) via intravitreal injection. Inactivation duration was assessed via contrast sensitivity function (CSF) in awake-behaving adults and visual evoked potential (VEP) responses in anesthetized infants. Safety of the TTX approach was investigated using optical coherence tomography (OCT), electroretinogram (ERG), retinal histology, and clinical evaluation of a relative afferent pupillary defect (RAPD).

RESULTS

Inactivation duration was dose dependent. Low doses (115-230 ng) resulted in up to 4 days of inactivation. Intermediate doses (460-920 ng) extended inactivation up to 8 days, whereas the highest dose (4800 ng) eliminated VEP responses for up to 10 days. RAPD that emerged soon after the injection was absent at about the same time as CSF and VEP responses recovered to baseline. Post-inactivation assessments using OCT, ERG, or histology showed no discernible changes in retinal structure or function.

CONCLUSIONS

Intravitreal TTX at the doses examined does not cause permanent disruption of vision in primates, and the duration of retinal inactivation can be titrated by dose. The dose-response relationship provides a foundation for future studies testing the efficacy of this treatment approach in amblyopic monkeys.