TEL AVIV, Israel - Ester Neurosciences Ltd., a development-stage company of the Medica Venture Partners Group in Tel Aviv, has introduced a new way of treating cholinergic-related neurological diseases such as Alzheimer's disease and myasthenia gravis.

Based on the award-winning work of Hermona Soreq, Ester's chief scientific adviser and head of the Eric Roland Center for Neurodegenerative Diseases at the Hebrew University of Jerusalem, the company is developing a way to prevent disease-induced modulation of acetylcholinesterase (AChE) gene expression. This modulation was discovered to play a fundamental role in the etiology of a wide range of currently incurable and highly debilitating neurodegenerative diseases.

Ester's scientists have shown that conventional AChE inhibitors actually up-regulate this modulation via a feedback loop, subsequently leading to long-term deleterious effects, not by the enzymatic effects per se, but via the morphogenic activity of a normally rare AChE variant that was discovered by Soreq and co-workers.

"These actions of the protein are completely unrelated to its catalytic functions in cholinergic transmission, but negatively affect the structure and function of nerve cells. The AChE protein affects neurite growth, cell-cell interactions and synapse functioning," said Soreq, who earlier this month was honored with the Minister of Health's Clinical Research Award for this work, which also relates to the Gulf War Syndrome.

Soreq told BioWorld International that chronic overproduction of this previously unknown AChE variant seems to lead to morphological deterioration followed by impairment of cognitive and neuromotor functioning, as well as in muscle fatigue, "phenomena that characterize patients with neurodegenerative diseases related to cholinergic malfunction.

Ester Neurosciences General Manager Oded Ben-Joseph, a neuroscientist graduate of Cambridge University in England, added, "These discoveries not only provide an exciting novel window for therapeutic intervention but also explain and predict the limitations of currently prescribed drugs given to Alzheimer's patients.

"Conventional inhibitors, as well as other insults, trigger the harmful accumulation of this previously unknown AChE variant. Our strategy is therefore to avoid excessive activation of the feedback response signal by blocking production at the pre-expression level. We have achieved this by designing a family of highly specific Anti-AChE antisense compounds," Ben-Joseph told BioWorld International.

One of these active antisense inhibitors, AS/3, was shown to possess high efficacy at low doses and over extended time periods when administered orally to myasthenic animals. This lead compound will soon enter human clinical trials.

Some further relief is about to become available to Alzheimer's patients in Israel. Responding to patient demand, the Health Ministry announced that within two months it will ease qualifying criteria to obtain medication through the health maintenance organizations for symptomatic treatment of Alzheimer's disease. Despite this, most Alzheimer's sufferers still will not be eligible for the currently available medicines.

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