Looking Drug Development Squarely in the Eye
Here on Eureka we talk a lot about the 3 Rs, the philosophy of replacement, reduction and refinement that we are committed to in all of our work. Many times the way we achieve these goals is through the development of new tools. But we are also always on the lookout for ways to use our existing processes in new ways that allow us to get the most information out of every experiment.
A prime example of this can be found in optical coherence tomography (OCT), a technique my colleague Dr. Mark Vézina has previously written about (here and here). While he focused on the use of OCT to examine the retina, especially in preclinical safety and toxicology studies, the technique can be used to obtain information about other parts of the eye.
OCT imaging can be done on the anterior segment of the eye – the front part of the eye bounded by the cornea and lens and including the iris, ciliary bodies and aqueous humor. Two primary assessments can be conducted: corneal thickness and iridocorneal angle.
To understand the power of OCT, consider two hypothetical scenarios:
A test article for a non-ocular indication has been shown to cause corneal thinning. A study can be designed to assess histologic changes in corneal thickness. Using Anterior Segment OCT, corneal thickness is measured during the in-life phase, as well as histopathologically. Furthermore, animals can be followed during a recovery period to assess when/if the change is reversed.
A series of lead compounds are being assessed for treatment of glaucoma. The efficacy of the leads could be assessed using histopathology, with eyes examined at various time points after compound administration. With OCT, we can reduce the total number of animals used by repeatedly imaging the same animals over time to assess iridocorneal angle. Each animal’s results at each time point can be compared back to its pretreatment values.
In addition to getting more data from each animal, OCT allows us to get better data overall. The multiple measurements from each individual animal reduce the effects of inter-animal variability, and allow trends to emerge, including transient effects. If animals treated with a test compound are examined only at the end of the experiment, one might not capture a transient change in iridocorneal angle that comes and then goes. This would represent a missed opportunity to gain important insight into the mechanism of the drug.
The eyes have been described as the windows to the world. With the noninvasive 2D and 3D imaging that OCT makes possible, they can also be windows to the vasculature of the eye, which in turn can yield important information about the overall vascular impact of a compound --especially those effects not easily assessed by blood pressure or ECG measurements. For example, a compound may cause localized vascular leakage, clotting (thromobosis) or vein occlusion. If these effects are detectable in the retinal vasculature, OCT can provide a non-invasive method of monitoring the effects over time.
Finally, in addition to detecting structural changes in the eye and the retinal vasculature, it might potentially detect brain lesions, since the retina and optic nerve are neuronal tissues.
OCT is clearly a powerful tool. Together with other assessments, the types of measurements it enables can give a fuller picture of the efficacy and safety profile of a drug candidate.