Improving Preclinical Suprachoroidal Injections

Abstract

Purpose : The suprachoroidal space (SCS) is a new route for delivering retinal therapeutics but, reliably reaching the SCS is not trivial. In clinical trials, failure to reach the SCS on first attempt occurred in 29% of patients when utilizing a perpendicular injection. Preclinical SCS injections are even more challenging with success rates as low as 50% where inadvertent intravitreal or subretinal injections are common. This study aimed to develop injectors optimized for rat and nonhuman primate (NHP) anatomy resulting in more reliable injections.

Methods : Novartis developed a novel SCS injector, TS Micro™, which tangentially accesses the SCS via a simple injection technique with one needle length. This design was scaled to accommodate the smaller eye diameter and thinner sclera of the NHP and rat. Devices were tested ex- and in-vivo by injecting trypan blue and indocyanine green (ICG) to confirm delivery to the SCS via direct visualization and histology. Rats were injected with volumes of 3-4µL and NHP with volumes of 100µL. Subsequently, NHP received bilateral injections of AAV8 at 6.6E10, 3.3E11, and 1.66E12 vg/eye. Vector biodistribution in the visual system was collected after 12 weeks.

Results : Delivery to the SCS was successful in both rat and NHP. Histology confirmed trypan blue was delivered to only the SCS in rats (Fig. 1) however the success rate remained at 50%. In vivo NHP cSLO imaging ICG confirmed SCS delivery with coverage consistent with human cadaveric testing (Fig. 1). Delivery of AAV8 further confirmed successful SCS delivery as vector copies were elevated in the RPE/choroid (Fig. 2). NHP SCS injection success was 96%.

Conclusions : Utilization of a tangential approach to the SCS and customization of the TS Micro™ device for preclinical animal anatomy allowed for reliable access to the NHP SCS. However, further refinement of the rat injector is needed to improve reliability. These results highlight the importance of adequately evaluating preclinical SCS injections to ensure candidate targets are delivered to the intended tissue.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

SCS injections in rat (A-B) and NHP (D). Histologic sections show dye (red arrows) in the SCS next to the RPE (A) identified with RPE65 staining (yellow arrow, C). Bilateral ICG injections visualized via cSLO IRAF (colorized) overlayed on cSLO IR imaging (D).

 

Biodistribution of AAV8 in NHP visual system.