Ocular Toxicity Expertise

 Species

• Rabbit : New Zealand White (albinos) and Deutch belted (pigmented).

       The rabbit, although belonging to lagomorphidae, is usually selected as a "rodent" species for the safety assessment of ophthalmologic products administered directly to the eyes by topical or intra-ocular routes. New Zealand White (NZW) rabbits are the most frequently used as they are widely available, easy to handle and their eyes are large. Pigmented Deutch belted rabbits are used when no study is conducted in another pigmented species (like dogs or primates), and when the drug may bind to interfere with melanin. The eyes of Dutch belted rabbits are smaller and these animals are less widely available than NZW rabbits...

• Minipigs

         The minipig is an appropriate non rodent species for the non clinical safety evaluation of ophtalmologic products. High quality animals of the same strain are available woldwide and they are easy to handle. Intravitreous administrations are easy to perform in this species. Contrarily to the dog and similarly to humans there is no tapetum in minipigs, wich may interfere with drugs.

• Monkeys

         The anatomy and physiology of the monkey eye is the closest of all experimental animal species to humans. The structure of the retina is similar to humans with the absence of tapetum, and the presence of a fovea. They accomodate and the ciliary muscle is well developed. However, for obvious ethical reasons, the use of monkeys should be strictly restricted to drugs, biologicals or devices whose receptor or mode of action is not present in the other animal species.

• Dogs

         Although extensively used for general toxicity studies of drugs given by oral or parenteral routes, the dog is usually not the best choice for assessing the non clinical safety of ophthalmologic products. The presence of a Zinc-rich and highly light-reflective tapetum behind the retina may interfere with drug distribution and with opthalmological examinations.

CIT experience in ophthalmology

Administration route expertise

• Topical
• Subconjunctival
• Intravitreal

      CIT masters all technical aspects of intravitreal injection procedures in rabbitsn minipigs and cynomolgus monkeys. Injections are performed as in humans behind the limbus through the sclera and ora serrata of the retina. We routinely inject volumes of 50 to 100 uL in rabbbits, minipigs or cynomolgus monkeys with almost no complications.

• Subretinal

       CIT partners with human surgeons to successfully perform this very challenging technique which allows delivery of gene therapy products to the retinal cells.

Comply with guideline requirements with a complete set of ophthalmologic investigations :

• Shirmer test

      The Shirmer test is a simple way to measure basic tear production. A standardized strip of filter paper is inserted inside the lower eyelid (conjunctival sac) and the length of moisture is measured after a standard 5 minute period.

• Slitlamp biomicroscopy

      The portable slit lamp biomicroscope provides magnified images of the anterior structures of the ocular globe including the cornea, the anterior chamber, the iris and the lens. Illumination modes (i.e. direct focal illumination which is used for the observation of vitreous structures) may be selected for adequate examination of structure and location of findings. The MacDonald-Shadduck scoring system is used for an objective and reproducible evaluation of the findings. CIT trains and qualify all scientists involved in these examinations for accurate detection and description of any abnormal finding and for consistency across observers. All examinations are performed under the supervision of a veterinarian ophthalmologist.

• Indirect fundus ophthalmoscopy

       Indirect ophthalmoscopy provides a wide magnified view of the retina and is used for the identification of lesions of the optic nerve, retinal vessels and cellular layers of the retina. This non invasive examination is routenely part of general toxicity studies in all species (mice, rats, dogs, minipigs and non human primates). CIT trains and qualify all scientists involved in these examinations for accurate detection and description of any abnormal finding and for consistency across observers. All examinations are performed under the supervision of a veterinarian ophthalmologist.

• Applanation tonometry
• Corneal esthesiometry

      The Cochet-Bonnet esthesiometer provides a non-invasive objective assessment of the sensivity of the cornea, which may be reduced bu local changes as corneal oedema or changes in the pH of the lachrymal film, or by lesions of nervous fibers.

• Ocular reflexes

Dedicated equipment for special investigations :

• Digital slit lamp photography
• Indirect fundus retinography
• Optical coherence tomography

       This new non invasive imaging technique provides transversal views of ocular tissues. These are acquired as part of the slit lamp or indirect ophthalmoscopic examinations and may be repeated over time in the same animal. The thickness and structure of the cornea, anterior chamber, lens, vitreous and retina can be explored with a level of detail comparable to histology. Lesions of the cornea as wells as retinal detachment or retinal atrophy may be easily quantified over time.

• Electroretinography (ERG) :

       Gantzfield electroretinograms are recorded and interpreted according to ECVO guidelines in photopic, scotopic and flickers conditions. These advanced investigations are performed by veterinarian ophthalmologists who have completed additional university training in electroretinography. The results of these investigations are reported as a contributing report.

Pharmacokinetics

• Validation using surrogate matrices and quantification of compounds in ocular tissues and fluids.

Staff

• 7 veterinarians pathologists and specialized ocular board certified consultants for electroretinography and special procedures.
• Highly trained technicians on anatomical samples for reliable administration.