Translatable animal model needed if glaucoma research is achievable

Animal models are vital to glaucoma research. The problem is that no single animal model fully recapitulates the natural history of human glaucoma, which is just as well. A model that mimicked the progression and time line of human glaucoma would do little to speed drug discovery.                                          

“Animal pre-clinical research is key to innovation and to finding a cure for this disease,” explained Andy Whitlock, PhD, vice president of pre-clinical research and development for Ora, an ocular drug and device-development company. “It’s easy to focus on the finish line, but it all starts back in the lab with an idea. Regardless of whether we’re talking intraocular pressure (IOP) or retina, we need to start with some sort of translatable animal model to have any hope of success in the clinic.”

Dr. Whitlock explored the ins and outs of “Animal Models of Glaucoma and Their Translatability in the Clinic” as part of the New Horizons Forum at the 2017 Glaucoma 360 meeting. There is no perfect animal model, he warned, but there are factors that make different models better in terms of translation into clinical research. The biggest problem is a lack of consensus which models are suited to which types of research.

“People are doing IOP studies with zebra fish and cows and monkeys and everything in between,” Dr. Whitlock said. “There is a real need for basic scientists and clinicians to come together to determine what really makes a meaningful model. Regardless of the species, animal models used in glaucoma research need to be based on clinical findings and understanding of the disease.”

Four criteria needed

In order to be useful and translatable to clinical research, animal models must meet four criteria, Dr. Whitlock outlined.

First, the model must possess the relevant pathology to answer the question being asked. Using rabbits to study the effect of latanoprost in reducing IOP is wasted effort because the agent is not effective in reducing IOP in rabbits. The same study, conducted in glaucomatous monkeys, could be highly translatable to clinical research.    

Second, the model must have predictable pathology and a timeline that is reasonable for pathologic screening. Whether transgenic or natural, the model must be pharmacologically relevant, predictable, and reasonable. A species that develops glaucoma over 20 years is not a useful model because of the time line.

Third, the model must be modifiable with the relevant treatments and has been validated with appropriate clinical comparators. Validation may not be a problem in IOP studies, but it remains a barrier in neuroprotection because there are no clinical agent comparators.

Fourth, the model must incorporate clinically relevant endpoints, whether the endpoints are biomarkers or clinical evaluations. Incorporating clinically relevant endpoints is less of a point today than in past decades, Dr. Whitlock said.

“One element that has improved is our ability to do useful things in animal models that was once possible only in humans,” he pointed out. “Pretty much anything you can do in the clinic, I can do in the lab with a mouse, a monkey, a rabbit.”

Benchmarking key

Benchmarking key

Benchmarking the model is a key step. Not just benchmarking the species but also the controls used. Timolol and latanoprost are used as comparators in mice, but pilocarpine is not.

“Once you realize mice do not have scleral spurs, you realize that you can constrict the pupil all day long with pilocarpine, but it is not going to tug on anything and affect outflow,” Dr. Whitlock said. “Benchmarking will tell you what a species can and cannot do in your research.”

Basic researchers must keep up with the latest clinical technology. Optic nerve crush models have long been used to assess retinal neuroprotection, but emerging technologies are changing the ways the crush model can be used.

Historically, optic nerve crush was evaluated by counting ganglion cells in a rat model or examining the thickness of the neural fiber layer. The emergence of optical coherence tomography allows researchers to perform those evaluations on a serial basis over the course of the study. Serial measurements help understand the functional consequence of the challenge and better evaluate any change.

Pharmacokinetics ignored

Pharmacokinetics are another area that is ignored.

“Regardless of the route and regardless of the indication, it is vital to determine ocular exposure and pharmacokinetic profile before interpreting efficacy studies,” Dr. Whitlock cautioned. “If you don’t get the drug to the target tissue, you’re not doing an experiment. Don’t confuse poor efficacy with poor drug delivery.”

Basic and clinical researchers recognize these potential pitfalls, he added, but they evaluate and deal with the issues in different ways. That lack of commonality hampers research and complicates translation of potentially useful preclinical findings.

“Understanding of the disease and the animal models can only be accomplished through open collaboration and discussion between all of us in the glaucoma community,” Dr. Whitlock said. “A consensus about the underlying causes and pathologies and direction of the disease need to be reached in order for the animal models to be relevant.”