Researchers develop new preclinical model of human ocular hypertension

A transgenic rodent model of ocular hypertension is showing promise as a new tool for assessing novel druggable targets for glaucoma treatment, said Martin B. Wax, MD, at the annual meeting of the American Glaucoma Society.

Dr. Wax spoke on behalf for his collaborators in Ophthalmology Discovery Research at Alcon Laboratories, Fort Worth, TX. He explained that the model was developed to mimic human ocular hypertension/glaucoma in the mouse. It is based on adenoviral vector transfection of the trabecular meshwork with proteins thought to be involved in causing outflow obstruction. The proteins being evaluated are identified as being upregulated in the trabecular meshwork of glaucomatous eyes compared with controls and then further tested for their functional effects. Subsequently, drugs targeting the specific protein are evaluated for their ability to prevent or reduce the IOP elevations induced by the protein overexpression.

Dr. Wax presented findings from proof of concept experiments performed using two proteins, serum amyloid A2 and secreted frizzled related protein 1. The results showed that overexpression of both proteins following transfection with an adenoviral vector resulted in significant increases in IOP in the animal eyes. Concurrent administration of a kinase inhibitor at the time of transfection with serum amyloid A2 mitigated the IOP increase. Animals transfected with sFRP1 developed ocular hypertension 7 to 10 days later, but the increased IOP was lowered dramatically when animals were treated topically with an enzyme inhibitor that antagonizes the sFRP1 pathway.

"Animal models for glaucoma are typically based on laser-induced destruction of the trabecular meshwork or obliteration of vessels in the episcleral outflow pathway in order to increase IOP," Dr. Wax said. "However, these models are probably not helpful for assessing the potential efficacy of new therapies designed to modulate the pathology of glaucoma in the trabecular meshwork.

"Further study is now needed to determine whether the transgenic models truly resemble human disease and to see if the elevations in IOP can be sustained to cause glaucoma in the mouse," Dr. Wax added. "However, the ultimate test and validation of whether these models really have utility requires research showing that drugs found efficacious in this model also work to lower IOP in man."