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Trabecular meshwork is the logical site for glaucoma gene therapy
Glaucoma may leap ahead of macular degeneration in the race toward application of gene therapy.
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KOLOA, Hawaii – Inserting a corrective protein gene into the trabecular meshwork of a glaucomatous eye could be the key to curing glaucoma permanently, according to a presentation here.
“There are many possibilities, for instance, if there is a known abnormality, we could correct this forever by inserting the gene forming the normal protein into the trabecular meshwork. Obviously we are not quite there yet, but it is something that with some optimism one can look toward in the future,” said David L. Epstein, MD, here at Hawaii 2001, The Royal Hawaiian Eye Meeting, sponsored by Ocular Surgery News in conjunction with the New England Eye Center.
Dr. Epstein, professor and chairman of ophthalmology at Duke University Eye Center, predicts that gene therapy for glaucoma or corneal endothelial disease will be available long before gene therapy for macular degeneration, despite the retina research community’s high-profile findings.
“It would be intuitive to all of you. If you gonioscope your patients and you see pigment in the meshwork and you ask, ‘How did that pigment get there?’ you will realize, as I did, that the trabecular meshwork is the logical site for gene therapy,” he said.
Ethacrynic acid
Many drugs of the ethacrynic acid family are under development by private manufacturers and licensed by Duke University. Ethacrynic acid was developed to change the architecture of trabecular meshwork cells and the geometry of the outflow pathway.
“Although successful in substantially lowering intraocular pressure (IOP) in vitro, in living animals and in one human study after intracameral injection, it was never suitable for topical administration due to poor corneal penetration. After failing intracamerally to blunt the postoperative IOP spike after cataract surgery, attention turned to developing new analogs in this class that could be suitable for topical administration, and this is currently under active development,” Dr. Epstein said.
The precise mechanism of action for these compounds was never fully defined, Dr. Epstein reported.
“Toward this goal, our group at Duke, under the direction of Terete Borras, PhD, has developed techniques of gene transfer/gene therapy directed at the trabecular meshwork to change one protein at a time in the tissue to specifically treat what is wrong. In living animals, it is possible to deliver into aqueous humor, without apparent toxicity, a modified adenovirus carrying genes that are taken up by outflow pathway cells, which results in new proteins being expressed,” he said.
The immunological privilege of the anterior chamber and the flow of aqueous humor into the outflow pathway make it feasible that gene therapy in the eye will first be utilized for the treatment of glaucoma.
“This will represent the ‘new pharmacology,’ which is a fitting legacy for the original concept of ethacrynic acid,” he said.
“I am optimistic that some potent new trabecular meshwork drugs might be available in the future. I still think a drug for the trabecular meshwork is the Holy Grail and offers a lot of potential for glaucoma therapy in terms of dampening fluctuation of IOP and maintaining long-term effects,” he added.
Gene therapy
Dr. Epstein provided a basic description of gene therapy.
“Gene therapy consists of taking a gene and ‘hooking it up’ with a vector, having the vector move into cells in the tissue and having the DNA incorporated into the DNA of the cell host,” he said. With respect to glaucoma, he said, “Especially in the trabecular meshwork where the cells do not replicate very readily, one could replace or add a newly expressed protein to whatever is going on in this tissue.”
The remaining piece of the puzzle is to what form should the cells be altered.
“What do you want these cells to make?” he asked. “For the first time, there has been a mutation in an abnormal protein called TIGR that has been linked to juvenile open-angle glaucoma and less than 5% of adult forms of primary open-angle glaucoma. The people who have these forms of glaucoma make, in their trabecular meshwork cells, an abnormal protein that interferes with the cell function. If one could use an appropriate TIGR gene with the adenovirus, one could theoretically restore normal function,” he said.
Are there other possibilities? “This brings us back to ethacrynic acid. If there are abnormalities in glaucoma such as cell tension, cell flaccidity or cell attachment, instead of getting a drug that does more than one thing, maybe one would put a specific protein in to correct this defect,” Dr. Epstein said.
For Your Information:
- David Epstein, MD, can be reached at Box 3802, Erwin Road, Duke Eye Center, Durham, NC 27710; (919) 684-5846; fax: (919) 681-6343. Dr. Epstein has a direct financial interest in ethacrynic acid, licensed by Duke University to Santen Pharmaceuticals.