Feasibility of intravitreal injections and ophthalmic safety assessment in marmoset (Callithrix jacchus) monkeys

Abstract

Abstract. To safeguard patients, regulatory authorities require that new drugs that are to be given by the intravitreal (IVT) route are assessed for their safety in a laboratory species using the same route of administration. Due to the high similarity of ocular morphology and physiology between humans and nonhuman primates (NHPs) and due to the species specificity of many biotherapeutics, the monkey is often the only appropriate model. To this end, intravitreal administration and assessment of ocular toxicity are well established in cynomolgus monkeys (Macaca fascicularis). In contrast, the common marmoset monkey (Callithrix jacchus) is not a standard model for ocular toxicity studies due to its general sensitivity to laboratory investigations and small eye size. It was the purpose of the present work to study whether the marmoset is a useful alternative to the cynomolgus monkey for use in intravitreal toxicological studies. Six marmoset monkeys received repeated (every 2 weeks for a total of four doses) intravitreal injections of 10 or 20 µL of a placebo. The animals were assessed for measurements of intraocular pressure (IOP), standard ophthalmological investigations and electroretinography (ERG). At the end of the dosing period, the animals were sacrificed and the eyes were evaluated histologically. ERG revealed similar results when comparing predose to end-of-study data, and there was no difference between the two dose volumes. A transient increase in the IOP was seen immediately after dosing, which was more pronounced after dosing of 20 µL compared to 10 µL. Ophthalmologic and microscopic observations did not show any significant changes. Therefore, it can be concluded that 10 µL as well as 20 µL intravitreal injections of a placebo are well tolerated in the marmoset. These results demonstrate that the common marmoset is an alternative to the cynomolgus monkey for intravitreal toxicity testing.

Anatomical variability, multi-modal coordinate systems, and precision targeting in the marmoset brain

“…For example, species with large eyes relative to the brain size (e.g., marmosets) tend to have a large or positive pitch (frontal downward direction) of the stereotactic coordinate relative to AC-PC plane, whereas species (e.g., human and macaque) with relatively smaller eyes tend to have a smaller or negative pitch (frontal upward direction). Indeed, the volume ratio of eyeball to brain is sub-stantially larger in marmoset (10%) ( Korbmacher et al, 2017 ) in comparison to macaque monkeys (3%) ( Atsumi et al, 2013 ) and humans (0.4%) ( Heymsfield et al, 2016 ).…”

Anatomical variability, multi-modal coordinate systems, and precision targeting in the marmoset brain

“…For example, species with large eyes relative to the brain size (e.g., marmosets) tend to have a large or positive pitch (frontal downward direction) of the stereotactic coordinate relative to AC-PC plane, whereas species (e.g., human and macaque) with relatively smaller eyes tend to have a smaller or negative pitch (frontal upward direction). Indeed, the volume ratio of eyeball to brain is substantially larger in marmoset (10%) (Korbmacher et al, 2017) in comparison to macaque monkeys (3%) (Atsumi et al, 2013) and humans (0.4%) (Heymsfield et al, 2016).…”