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March 2006

News in Review
A Look at Today's Ideas and Trends
By Linda Roach, Contributing Writer
Edited by Brian A. Francis, MD

• Keeping an Eye on Parkinson’s Disease
• Cream Holds Promise for Treating Eyelid Cancer
• Glaucoma Caused by Tiny Buckyballs? Maybe
• Retina Report: Treat AMD as a Two-Part Disease

Keeping an Eye on Parkinson’s Disease

When neurologists performed cell implants to increase dopamine in the brains of Parkinson’s patients, the neurons in question were derived from human retinal pigment epithelium. But why RPE?

Because a large body of painstaking work over the last three decades has found that retinal pigment epithelial cells produce levodopa, the same drug used to combat the dopamine deficiency of Parkinson’s. However, oral dosing with levodopa causes spikes and troughs in dopamine levels, which are thought to underlie a troubling side effect of treatment: motor fluctuations and dyskinesias as the dopamine levels vary.

Isolated from cadaver eyes, expanded in number by a proprietary process and attached to gel microcarriers to keep them healthy, the RPE cells were implanted in the brains of six Parkinson’s patients. One year after surgery, the patients scored an average of 48 percent better than before on the standard scale for rating Parkinson’s symptoms.1

The study’s sponsor, Titan Pharmaceuticals, consequently has begun a larger phase 2b efficacy study—randomized and masked this time—for the cell-based drug implants, which the company calls Spheramine.

As the trial progresses, it will continue to shine a light on dopamine in the retina and on the role played by amacrine cells, a class of retinal neuron located at the border of the retina’s inner nuclear and inner plexiform layers. In ophthalmic textbooks, amacrine cells rate only passing mention for mediating some "on" and "off" signals to photoreceptors and ganglion cells.

But in recent years, it has become apparent that one subtype of amacrine cell is the source of retinal dopamine and has much to teach about a complicated set of dopamine-dependent ocular processes, according to Paul Witkovsky, PhD, professor of ophthalmology and of physiology and neuroscience at New York University.

Dr. Witkovsky published a 2004 review article that details the new knowledge about dopamine’s importance in the retina.2 This includes a circadian cycle that—paired inversely with melatonin—regulates the time of day or night during which either cone or rod photoreceptors control vision. (How the levodopa produced by the RPE cells fits into this picture is not known.)

"At least some members of every major class of retinal neuron have dopamine receptors, as do retinal pigment epithelial cells, Müller’s glial cells and pericytes," he writes. "Diffusion carries dopamine to the remotest corners of the retina. Somehow the multiple actions of dopamine are coordinated to produce an integrated result, which is to prepare the retina for daytime vision."

Indirect evidence of this comes from the fact that Parkinson’s patients often show deficits on the pattern electroretinogram test, the article notes. It also elucidated a series of animal experiments identifying dopamine and its receptors as possible mediators of eye growth leading to myopia.

"As the eye starts to see in a newborn, the act of focusing is important in getting the eye to grow to be its correct, round shape," Dr. Witkovsky said. "It appears that the retina, sensing focus, sends some kind of a chemical signal to the RPE, which in turn sends a signal off its basal end to the sclera, telling it to grow. The signal might or might not be dopamine, or not just dopamine, but the mechanism is clear."

Does dopamine underlie this trigger for ocular growth? Might disturbances in its circadian fluctuations be involved in age-related difficulty with night vision? What about visual effects from dopamine agonists or antagonists taken as medication? It’s too soon to tell, Dr. Witkovsky said. But this work seems to reveal a need for clinicians to be alert for predictable, dopamine-related deficits in retinal function, even when the Parkinson’s patient has more pressing concerns related to movement disorders.

1 Stover, N. et al. Arch Neurol 2005;62:1833–1837
2 Witkovsky, P. Documenta Ophthalmologica 2004;108:17–40.

Oncology News

Cream Holds Promise for Treating Eyelid Cancer

Skin cancer on an eyelid presents a patient with a difficult course of treatment that leads to ophthalmic plastic surgery in this delicate area, which can take a year to heal. Sometimes the location or size of the tumor precludes surgery.

So even a two-patient study showing the disappearance of large nodular basal cell carcinomas after application of an immune-modulating cream was notable enough to gain publication in the American Journal of Ophthalmology.1 A year after treatment in this Italian trial, the patients, both in their 80s, showed no visible evidence of recurrence, though this was not confirmed histologically.

The FDA approved the drug, imiquimod 5 percent (Aldara), in 2004 for use against superficial basal cell carcinomas not located on the face. It stimulates monocyte/macrophage production of interferon-alpha and other immune cytokines, leading to a two-year clearance rate of nearly 80 percent of superficial skin cancers.

Currently, several European trials are testing whether imiquimod works in nodular basal skin cancer. However, its common side effect of skin irritation, sometimes severe, has led to caution in using it on the face.

"Imiquimod has revolutionized the treatment of cutaneous tumors," said Carol L. Shields, MD, associate director of the ocular oncology service at Wills Eye Hospital in Phila- dephia. "This medication stimulates the body’s own cutaneous immune system to fight malignancy. But application to the periocular region should be cautious."

The AJO study illustrated the reasons for Dr. Shields’ caution, as well as the potential for positive results. It was done in two patients who refused surgery for nodular basal cell tumors.Three times a week, the patients applied the cream, leaving it on for eight hours and then washing it off.

One patient had to stop treatment on his lower eyelid for two weeks because of conjunctival inflammation and superficial punctate keratitis. After those resolved, he applied the cream again, for a total of 12 weeks. The eyelid of the other patientshowed skin irritation and flaking, but she was able to continue treatment for eight weeks.

1 Blasi, M. A. et al. Am J Ophthalmol 2005;140(6):1136–1139.

Glaucoma Research

Glaucoma Caused by Tiny Buckyballs? Maybe

A decade after they were first detected in cultured trabecular meshwork cells, "buckyball"-shaped molecules made from the cytoskeletal protein actin might be pointing at a new molecular pathway toward glaucoma treatments.

With a shape usually described as a soccer ball or a geodesic dome (thus buckyballs, after dome inventor R. Buckminster Fuller), these rigid assemblages of actin molecules were first detected in the mid-1990s in trabecular meshwork (TM) cells that had been cultured with dexamethasone.1

At the time, a team led by Abbot F. Clark, PhD, senior director of glaucoma research at Alcon Research Ltd., speculated that cross-linked actin networks (CLANs) made the TM cytoskeletons more rigid and thereby altered TM cell function. This would explain why corticosteroids can raise IOP, they say.

Eliminating the CLANs would be a logical target as a way to normalize the TM structure to restore fluid drainage, Dr. Clark said. "This would be a completely different mechanism of action for glaucoma drugs—potentially, an actual disease-modifying therapy," he said.

The idea of CLANs as a cause of glaucoma had lain fallow until last year, when confocal laser scanning microscopy experts at the University of Liverpool and the University of Toronto joined with the Alcon team to look for CLANs. They found actin buckyballs not only in cultured cells, but also in anterior segments that had been perfused with dexamethasone.2 Since then, the Liverpool and Alcon scientists have confirmed that these same CLAN structures occur in glaucomatous eyes, Dr. Clark said.

"We have yet to prove that CLANs are the cause of glaucoma," he cautioned. "But I have a graduate student working on that project right now. Once we identify what proteins are causing the CLANs, we can do some experiments to see if altering their expression will prevent CLAN formation and restore aqueous outflow."

1 A. F. Clark et al. Invest Ophthalmol Vis Sci 1994;35(1): 281–294.
2 A. F. Clark et al. Cell Motil Cytoskeleton 2005;60(2):83–95.

Retina Report:
Treat AMD as a Two-Part Disease

Ophthalmologists are suffering from an embarrassment of riches in treatments for age-related macular degeneration these days.

What’s needed now, said New York City vitreoretinal specialist Richard F. Spaide, MD, is a conceptual framework for evaluating which treatments make the most sense to combine with one another.

"In ophthalmology, we’re not that experienced in the idea of combining therapies," Dr. Spaide said. "It’s like the early days of cancer therapy. It took oncologists some time to become very sophisticated about putting different chemotherapy combinations together in a rational way." He suggests that the experimental period in which ophthalmologists determine which different treatments can be used synergistically might be shortened if choroidal neovascularization is viewed as a two-pronged disease:1

  • The vascular component, consisting of endothelial cells, circulating endothelial progenitor cells and pericytes. This is the main component of CNV and the one that photodynamic therapy and the drugs Macugen and Lucentis address.
  • An extravascular component, made up of inflammatory cells, fibrocytes, myofibroblasts, retinal pigment epithelial cells and glial cells. So far, intravitreal corticosteroids have been the only treatment to target this aspect of the disease.

His conceptual framework suggests a theoretical risk that some therapeutic combinations would be counterproductive. For instance, an inhibitor of vascular endothelial growth factor might prevent healing of normal choroidal blood vessels damaged by PDT, he said. On the other hand, combining a VEGF inhibitor with corticosteroids would represent two different attacks on the vascular component and one against the extravascular component.

1 Spaide, R. F. Am J Ophthalmol 2006;141(1):149–156.