Source: J Indian Med Assoc  |  Posted 7 years ago

By Mike Fillon

FORT LAUDERDALE, FL -- May 3, 2004 -- There have been significant advances in understanding the mechanisms behind the death of retinal neurons and in the development of neuroprotective therapies for glaucoma and other neurodegenerative diseases. A panel of leading researchers provided an update on that progress here on April 25th at the Association for Research in Vision and Ophthalmology Annual Meeting.

Mathias B?ehr, MD, University of Goettingen, Goettingen, Germany, reviewed research relating to signaling of retinal ganglion cell death after axonal damage. Studies using a preclinical model show the mechanism for retinal ganglion cell death after traumatic axonal injury involves full-blown activation of the apoptotic machinery. That experimental system has also allowed characterization of associated molecular events and thus identification of potential strategies for interfering with the apoptotic cascade.

Studies to date have investigated the potential utility of several approaches to neuroprotection, including application of neurotrophic factors, erythropoietin, and agents to inhibit caspase activation, Dr B?ehr said. Recently, attention has focused on inhibition of cyclin-dependent kinases (CDKs), molecules important for mitochondrial integrity, and results of experiments with that approach have been promising in showing their ability to prevent mitochondrial dysfunction and protect against cell death, he said.

Another new strategy has aimed to use viral vectors to induce overexpression of Bcl-X(L). "With this technique, we have extended cell rescue over 8 weeks, and perhaps in the future, we might combine approaches to achieve enhanced and longer-term protection," Dr. B?ehr said.

Later in the symposium, Scott M. Whitcup, MD, of Allergan, in Irvine, California said the clinical development of neuroprotective agents presents unique challenges, but recognition of those obstacles provides direction for research that may culminate in the identification of safe and effective drugs.

"Important progress has been made in neuroprotection. The first neuroprotective drugs are here, and more are sure to follow," Dr. Whitcup said. Riluzole (Rilutek) is now available for the treatment of amyotrophic lateral sclerosis, and memantine (Namenda) is on the market for the treatment of Alzheimer's disease and in glaucoma phase 3 studies, he said.

Outlining some of the considerations that are important in the development of neuroprotective drugs, Dr. Whitcup cited the importance of well-designed preclinical studies to test mechanism of action and identify proper dosing strategies. In addition, investigations need to be performed to assess drug absorption, distribution, metabolism, elimination, and toxicity (ADMET). "Nine out of 10 drugs that begin development fail to reach the clinic, and about half do so because of problems with ADMET," Dr. Whitcup said.

Michael Schwartz, PhD, Weizmann Institute of Science, Rehovot, Israel, reviewed ongoing research focusing on vaccination as a neuroprotective strategy for glaucoma.

"While numerous factors have been identified as contributing to the process of degeneration that occurs in glaucoma and other neurodegenerative diseases or acute insults to the CNS [central nervous system]," said Dr. Schwartz, "pharmacological approaches target individual mediators to slow or halt progressive cell death. Vaccination aims to harness the immune system for the benefit of the glaucomatous optic nerve and represents a single immunologic intervention to fight off all of the mediators."

Dr. Schwartz noted that glaucoma is neither an inflammatory disease nor an autoimmune disease, but the rationale for use of vaccination as neuroprotective therapy for glaucoma is based on recognition that the immune system plays a pivotal role in recovery from CNS injury. Acting as a local buffering system, it is controlled by non-neuronal cells, including resident microglia, which if suitably regulated, buffer harmful self-compounds and prevent the formation of other noxious agents or events, including glutamate, nitric oxide, and activation of the cyclooxygenase 2 enzyme.

Dr. Schwartz also said that ongoing vaccination studies for glaucoma are being performed with copolymer-1 (Copaxone, Teva), a vaccine that is currently on the market for the treatment of multiple sclerosis. Available data from the glaucoma studies indicate copolymer-1 acts as a weak agonist of a wide range of self-reactive T cells, evoking a systemic T cell response that provides protection both in the eye and in the brain. In preclinical testing performed in models of acute and chronic intraocular pressure elevation, the treatment has been demonstrated to have positive effects on cell morphology as well as for preserving function as measured by pattern electroretinogram studies.

"This one antigen can benefit multiple causes of neuronal loss, and that is important for glaucoma, which is a disease affecting sites in the brain as well as in the eye," said Dr. Schwartz. "Our hope is that at another neuroprotection symposium held 5 years from now, we will be able to inform you that this strategy works in patients."

[Presentation title: Neuroprotection: Where Are We Now. Posters 20, 24, 23.]