Genetic modification of trabecular meshwork explored

Fort Lauderdale, FL-Gene transfer therapy is being studied to explore the pathophysiology of glaucomatous increases in IOP and identify new target genes and delivery mechanisms for treating glaucoma in the future, said Abbot Clark, PhD.

“The trabecular meshwork is the major source of ocular outflow,” said Dr. Clark, of the North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth.

“It imparts a natural resistance to outflow that maintains a homeostatic IOP,” he said. “In glaucoma, defects in the trabecular meshwork lead to increased outflow resistance and elevated IOP.”

The trabecular meshwork is advantageous as a target because it is readily accessible for injections into the eye, and prolonged transgene expression with the adeno-associated virus can be achieved. Disadvantages include an induced ocular inflammatory response and limited tranfections with plasmids and liposomes, Dr. Clark said.

Models used for gene transfer to the trabecular meshwork have included cultured trabecular meshwork cells, anterior segment perfusion culture, and in vivo animal models. Vectors have also been used for the same purpose.

Despite its accessibility, the trabecular meshwork cells are difficult to transfect, but viral vectors can increase delivery, he noted.

“Gene delivery to the trabecular meshwork can be long-lasting with adenovirus,” he said.

A number of genes are thought to be involved in glaucoma pathogenesis, including TGFB2, mutant MYOC, SFRP1, GREM1, SAA2, and COCH, and these elevate the IOP. The pressure can be lowered by gene transfer to the trabecular meshwork, which suggests new targets for glaucoma therapy.

“The trabecular meshwork is important for regulating aqueous outflow and glaucomatous IOP increases,” Dr. Clark said. “Gene delivery to the trabecular meshwork is useful to understand outflow biology, validate pathogenic pathways, generate animal models that are useful to glaucoma, and develop new therapeutics.

“The future is very exciting,” he added. “Some challenges include the discovery of vectors and trabecular meshwork-specific promoters for more specific transduction of the trabecular meshwork and to determine which genes to target.”

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