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Neuroprotection may become an alternative treatment for glaucoma
Some research is focusing on neuroprotective therapies and stem cells, not just lowering IOP.
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The prevention of retinal ganglion cell death with neuroprotective therapies that focus on factors other than IOP could be the future of glaucoma treatment, according to some physicians.
 Robert N. Weinreb |
While specific medications are in trials to treat glaucoma from a neuroprotective angle, other possible treatments are in less advanced stages of development, including other drugs and stem cell research, according to S. Fabián Lerner, MD.
 S. Fabián Lerner |
OSN Glaucoma Section Member Robert N. Weinreb, MD, said clinicians are examining ways to block damage to not only the optic nerve, but also the visual pathway, in both early and advanced stages of glaucoma, by delaying retinal ganglion cell death.
At the Advances in Glaucoma International Symposium in Argentina, which Dr. Lerner conducted, Dr. Weinreb said conventional glaucoma therapy focuses only on lowering IOP. However, lowering IOP alone does not prevent further progressive field loss in all patients because of other factors, a problem that neuroprotection seeks to address, he said.
“Glaucoma is recognized now as a progressive neurodegeneration, rather than just a condition related to IOP. We also recognize that it affects not only the eye, but the entire central visual pathway, including the brain stem and the brain,” Dr. Weinreb said. “Various interdependent factors contribute individually or collectively to a primary injury that is followed by a cascade of events.”
Neuroprotective drugs
Dr. Weinreb said that some available glaucoma drugs have had neuroprotective effects in experimental models, but prescribed drugs now address IOP reduction only. He said neuroprotective treatment focuses on saving retinal ganglion cells from dying, which available drugs have not been demonstrated to do.
Because some glaucoma patients may have more than one factor contributing to ganglion cell death, each factor must be effectively addressed, enhancing the survival of ganglion cells, he said. Factors that could cause ganglion cell death include deprivation of neurotrophic growth factors and presence of oxidative stress, nitric oxide and glutamates.
In animal research, the signal that has been most successfully targeted and altered in a primate model is glutamate, Dr. Weinreb said.
“When it’s present, it increases the influx of calcium into cells that causes them to be damaged and die by apoptosis,” he said.
Memantine, a drug on the market to treat Alzheimer’s disease, has been investigated as a potential treatment for glaucoma as well, he said.
Memantine targets the glutamatergic system, he said, protecting neurons from shrinkage in primate glaucoma. In monkeys, the drug prevents loss of retinal ganglion cells, optic nerve fibers, neurons in the lateral geniculate nucleus and neurons in the visual cortex. Results from a recent clinical trial should show whether memantine is useful in treating human glaucoma, Dr. Weinreb said.
Stem cell research
In a postgraduate course on glaucoma treatment, Dr. Lerner said that stem cells may enhance glaucoma neuroprotection. In an e-mail interview with OSN, he said stem cells might provide a new chance for restoring sight to patients who have lost some of their vision to the disease.
Stem cell research is still in its early stages, as researchers in Latin America and countries such as Singapore, China, Sweden and the United Kingdom are starting to receive funding and support, he said.
“Stem cells can be obtained from adults or from embryos. The use of embryonic stem cells is discussed and feared,” Dr. Lerner said. “This fact has direct consequences on the investment on research, at least in the United States. Research on the use of stem cells in the treatment of glaucoma is also affected by these factors.”
In 2006, President Bush vetoed a congressional act to extend embryonic stem cell research. Dr. Lerner cited an article published in The New England Journal of Medicine by Robert S. Schwartz, MD, that highlighted the stem cell debate in the United States. Dr. Schwartz said the veto, plus the ethical debate regarding embryonic stem cells, has effectively limited research in the United States.
However, in countries where research is moving forward, stem cells appear to be promising for numerous reasons, Dr. Lerner said.
Although much of this research is focusing on the central nervous system, he explained that the visual system is a “privileged site for investigation on the potential use of stem cells and the possibility of neural regeneration in mammals.”
Dr. Lerner said that stem cell research of the visual system should be pursued because physicians have an adequate knowledge of the retinal anatomy and its connections. In addition, there are sophisticated methods of functional and structural diagnosis, which may detect and evaluate the progression of diseases. He also said it is easier to quantify regeneration, plasticity and connectivity of retinal ganglion cell axons due to the system’s structure compared with other areas of the central nervous system, and intravitreal access is available for retinal ganglion cells and the optic disc.
Citing Levin and colleagues, he outlined potential treatments for glaucoma using stem cells in four different areas: the trabecular meshwork, retinal ganglion cells, the optic nerve and the lateral geniculate body.
Using stem cells in the trabecular meshwork might not aid visual recovery, it but could help lower IOP by repairing or replacing the trabecular meshwork cells. Dr. Lerner said research shows that certain cells in apes appear to act as stem cells and could become phenotypically close to trabecular cells if near the trabecular meshwork.
“These stem cells might be of adult or embryonic origin,” he said. “The latter, though potentially more available, might show an unlimited proliferation and even block the meshwork, making the situation even worse. It is necessary to know the precise role of the stimulating, inhibiting and differentiating factors working on these cells.”
Stem cells could possibly replace retinal ganglion cells, but that treatment poses risks, Dr. Lerner said. Stem cells would have to be placed in the correct location, and cortical adaptation would be required. Other possible problems include elongation of axons to reach the lateral geniculate body, formation of synapses and immunological issues, he said.
Using stem cells to repair the damaged optic nerve seems a more feasible option, Dr. Lerner said. He said it might be possible to repopulate the optic nerve with stem cells, rebuilding the structural matrix. Stem cells might also assist the optic nerve in leading axons to the lateral geniculate body.
For more information:
- S. Fabián Lerner, MD, can be reached at Marcelo T. de Alvear 2010, piso 2 D C1122AAF, Buenos Aires, Argentina; 54-911-4417-1392; fax: 54-11-4961-9258; e-mail: fabianlerner@fibertel.com.ar.
- Robert N. Weinreb, MD, can be reached at the University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093; 858-534-6290; e-mail: weinreb@eyecenter.ucsd.edu.
References:
- Levin LA, Ritch R, Richards JE, Borrás T. Stem cell therapy for ocular disorders. Arch Ophthalmol. 2004;122(4):621-627.
- Schwartz R. The politics and promise of stem cell research. N Engl J Med. 2006;355:1189-1191.
- Erin L. Boyle is an OSN Staff Writer who covers all aspects of ophthalmology.