January 1, 1970 (Vol. , No. )

Mark Vezina Charles River Laboratories

The benefits of optical coherence tomography will open your eyes.

Optical coherence tomography (OCT) is a noninvasive imaging technology that allows for a cross-sectional view of the retina, the retinal-vitreal interface, and anterior ocular structures at near-cellular resolution. In the clinic it is used to diagnose and follow ocular degenerative diseases, but in preclinical studies it can be used to help evaluate pharmacological or toxicological drug effects.

Below are five reasons why OCT should be considered for inclusion in a preclinical toxicology study:

  1. OCT is noninvasive: OCT imaging requires a relatively still subject, which for animals may require sedation or anesthesia. However, once anesthetised, all that is needed for the instrument to acquire an image is an open eye. The rapidity of acquisition (just a couple of seconds) and the noninvasive nature of the technique allow for reduced animal stress, as well as imaging of a relatively large number of animals in a single day.
  2. OCT permits longitudinal follow-up of a localized ocular dose: Many gene- and cell-based therapies require a localized dose near the site of therapeutic interest. In the eye, this often involves a depot delivery such as subretinal injection and therefore manipulation of critical ocular structures. OCT can provide sequential images of these manipulations from the time they are created to the end of the study. These types of studies often support prolonged therapeutic action after a single dose. Using OCT to sequentially observe the retina or anterior ocular structures over several months can reduce the numbers of animals required compared to traditional toxicology study methods.
  3. OCT can elucidate an observation from an ophthalmic examination (OE): Many different drug-induced OE observations seen in preclinical studies are similar in appearance when traditional indirect/direct ophthalmoscopy is used to visualize the retina. This can be true for toxicology studies using ocular dosing or systemic dosing. OCT can image the lesion and reveal the cell layers that are specifically affected, as well as whether or not the effect extends beyond what could be observed during the OE.
  4. OCT can detect some ocular lesions before they become evident with an OE: Changes in the outer retina are often not visible during an OE until they develop into a larger, more serious lesion. Theoretically, the real-time imaging capability of OCT could allow for scanning of the retina for potential early degenerative changes, but this is usually not practical due to the large area to be scanned. However, if the potential for a specific type of lesion is known to exist (perhaps from a previous study or compound class effect) and a geographic area is known, OCT can be a powerful tool. It becomes especially useful when an OE has detected a lesion in the high-dose group but nothing at the lower-dose levels. OCT may be able to detect early lesions in the lower-dose groups. Again, in this scenario longitudinal evaluation of the eyes with OCT can provide useful information on lesion development and safety margins over the course of the study. Furthermore, using OCT for longitudinal evaluation when the lesions are first detected can provide enough information to allow the original study to continue, thus reducing the need for further animal use.
  5. Preclinical OCT can aid in clinical trial study design: The high resolution and detail in OCT allows clinicians to use preclinical images to help design clinical trials. By showing the lack of change or the nature/location of changes in animal studies, OCT allows for risk assessments that take into account the structure-function relationships in the eye and the relevance of the animal anatomy to human anatomy in conjunction with the dosages administered. Effects in the animal models captured by OCT can then be screened using the same technology in humans as an additional safety monitoring parameter.

In summary, OCT can be a useful technology for both ocular and systemic preclinical toxicology studies by providing an in vivo, noninvasive, near-histopathology quality ocular image with the capacity for clinically relevant longitudinal evaluations of drug- or procedural-induced ocular lesions. Its sensitivity allows it to detect small defects not always visible during a routine ophthalmic examination, and in some instances its can reduce the number of animals needed in a preclinical toxicology program.

Infrared fundus image of minipig (left) with corresponding OCT (right). The bright green line on the fundus image represents the location of the OCT image.

Mark Vézina is the scientific director of the Ocular and Neuroscience Department at Charles River’s preclinical site in Montreal. Mark is an active member of the Ocular Toxicology Specialty Section of the Society of Toxicology (past president) and a regular contributor to the Ocular Research Group on Linked-In. For more information on OCT, contact Charles River ([email protected]).

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