Using Optical Coherence Tomography to image the animal eye in a preclinical space generates more translatable data, helping drug developers’ better design and monitor clinical trials and bring drugs to market faster
Ocular diseases such as Age-Related Macular Degeneration or Glaucoma are often photographed with Optical Coherence Tomography (OCT), an imaging device for obtaining real-time 2D and 3D cross-sectional images of the eye. This technology, which is rapidly becoming the gold standard for ophthalmic evaluations in retina and glaucoma patients, has been used in the clinic since the early 90’s, but has only recently moved into the preclinical space where it’s used to image the eye of animals in the assessment of therapeutics.
Optical Coherence Tomography works by aiming an infrared laser beam through the cornea and lens and onto the retina at the back of the eye. This light source reflects off cell layers of the retina and back into a sensor, which captures 40,000 scans a second. Like MRI reflects bone and tissues of different densities, OCT produces an image based of the differing densities of cells within the eye. Because of the extraordinary magnification and the natural, rhythmic movement of the eye with every heart beat, motion through the camera is exaggerated, much like a far-away image through binoculars bounces with slight hand movements. A sophisticated algorithm accounts for this by condensing the large number of scans to assemble a sharp image, giving the scientist 2D cross-sections of the retina or 3D composites produced from multiple 2D images [See Picture]. Using the 3D image, the researcher can scroll in all planes looking for lesions or other abnormalities.
Historically, preclinical evaluations of the eye have been conducted using the common histopathological examination, a way of analyzing the animal eye by creating cross-sections of tissue post-mortem for examination under a microscope. The recent move to OCT imaging in animals may in certain cases reduce the reliance on this time-consuming procedure. In addition to being able to obtain non-invasive, real-time pictures of the eye, images from OCT come in high resolution (approximately 10 microns), helping researchers screen compound effects in great detail, thus leading to more translatable data to humans, enhanced decision-making during clinical trial planning, and ultimately improved clinical trial outcomes.
In a preclinical setting, OCT can be used for multiple screening applications in animals. Often, it’s used to determine if the retina is properly attached, as it can sometimes be raised or detached in response to a treatment, surgery or compound. Measuring retinal detachment, OCT can be used to monitor how long elevation persists, whether folds are present, or whether the area reattaches properly. You can also look at whether certain bands of cells are abnormally thin, indicating cell death or atrophy, or abnormally thick, as is the case with edema or fluid accumulation. The imaging technology is particularly useful after sub-retinal injections of therapeutics, such as with an injection of cell-based or viral vector-based products. You can look into the eye’s vitreous humor too, the gel-like fluid inside the eyeball. In some surgeries this fluid is actually removed from the eye and replaced with a gas bubble or another fluid. In situations such as these, OCT can be used to monitor surgical aid devices used in the procedure.
In general toxicology studies, OCT can be used to monitor non-ocular drugs, known from the literature or from previous preclinical studies to be in a class of compounds with possible ocular side effects. This is true in the case of some Central Nervous System (CNS)-targeted drugs, which may result in hard-to-detect side effects during a routine ophthalmology examination (due to the limited surface view of the retina), but may be evident in OCT where the full depth of the retina can be observed. Because the same animal can be imaged in chronic fashion, the progression or regression of ocular changes can be monitored over time in the same animal. This ability has the potential to reduce the number of animals used depending on the design and purpose of the study. Particularly for non-ocular compounds, the demand for the inclusion of OCT assessments in preclinical studies has increased 100% over the past year. This is likely a result of an increase in the number of therapeutics currently being progressed that specifically targeting the CNS, which has a similar barrier system to certain molecules as the eye.
Used in a preclinical situation, OCT can complement histopathology. An advantage of OCT however, is that it is non-invasive and can provide data on a large region of the eye. The histopathology equivalent, known as step sectioning, is a much more labor-intensive process. When compared to routine histopathology the major drawback to OCT is its resolution. While the imaging technology has made leaps and bounds in this regard, image resolution is not yet at the cellular level like with histology. Every year there are improvements made to OCT however, and it’s likely that within the next ten years we will see OCT images with cellular resolution.
Ultimately, using OCT in a preclinical context produces animal data that is highly translatable to the clinic. That is, adverse events found for a drug candidate in early development can be tracked and monitored using the same technology later in a human during clinical trials. Overall, OCT is another tool drug developers have to reduce the number of animals used in a preclinical study, generate more useful and translatable data and thus design more effective clinical trials, improving the outcome of bringing a drug to market.
Caption: 3D colorized image of a mini-pig retina through OCT imaging, showing the optic nerve, retinal surface blood vessels and a cross-sectional view of retinal cell layers.
Mark Vézina is the Scientific Director of the Ocular and Neuroscience Department at Charles River’s preclinical site in Montreal. With over 21 years experience he has authored/coauthored numerous publications and has lectured on various topics related to the development of ocular therapeutics at scientific conferences, academic institutions and pharma/biotech companies. 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.