TEL AVIV, Israel - Israeli biotechnology company Ester Neurosciences Ltd. launched into the virtual world, placing its bid in the public arena for a genetic-based solution to neurological diseases.
Oded Ben-Joseph, general manger for Ester Neurosciences Ltd., told BioWorld International, "Therapeutics of most neurological ailments, including Alzheimer's disease and myasthenia gravis, remain largely palliative, leaving unmet an immense clinical demand for novel disease-modifying strategies."
"Treatment of Alzheimer's disease, for example, uses acetylchoinesterase (AChE) inhibitors to preserve transmitter acetylcholine (ACh) levels in hypofunctioning cholinergic neurons," said Hermona Soreq, chief scientific adviser for Ester. "This enzyme-inhibitor therapy has been clinically frustrating."
Ester scientists said they appear to have discovered why, and also how to manage the disease effectively.
Ester has shown that conventional AChE inhibitors (as well as physical trauma and psychological stress) trigger a feedback loop upregulating the read-through isoform of AChE (AChE-R). Soreq's research showed that excessive production of the AChE protein creates long-term structural and growth damage, impacting synapse formation, adhesion and maintenance, with consequent functional neuronal degeneration.
To control this feedback loop, Ester took a pre-expression, genome-based approach. It developed a family of antisense compounds as well as a high-throughput screening method that has been shown in animal models to control AChE biosynthesis.
"This new paradigm provides a novel disease-modifying approach for the treatment of a wide range of neurological diseases because it simultaneously preserves ACh levels while controlling the unwanted long-term damages triggered by overexpressed AChE," said Soreq, the year 2000 recipient of the Israel Ministry of Health Prize for Excellence in Biomedical Research. She also predicted that pre-expression inhibition of AChE may also prove therapeutic for amyloid-induced neuropathology because "AChE and Ab [amyloid] work in concert in a vicious cycle, which ultimately leads to progressive neural deterioration."
"Taken together, Ester's discoveries indicate that perturbation in AChE regulation may constitute a fundamental causative factor in the diseased state as well as a significant exacerbating factor working in concert with other pathological processes," Ben-Joseph said.
Ester's high-throughput system (HTS) is a cell-based immunoassay, a tool to rapidly screen for the potential disease-arrest properties of large numbers of small molecules able to control AChE expression while easily permeating the blood-brain barrier.
"We believe that our HTS will not only generate drug candidates in a time- and cost-effective manner to fill the company's pipeline, but will also provide a multitude of opportunities for corporate deals," said Ester CEO Eli Hazum, a former professor at the Weizmann Institute of Science in Rehovot.
Ester has begun working on myasthenia gravis using its antisense lead compound, EN101. Conventional AChE inhibitors generally have short-term activity (two to four hours) and often are administered five to nine times daily, but EN101's duration is more than 40 hours, the company said. Testing in myasthenic animal models has demonstrated high efficacy and safety with very low doses.
Jon Sussman, a neurologist at the Neuroscience Center at Hope Hospital in Greater Manchester, UK, who had participated in the animal studies, said he was "extremely impressed" by the results and, "If a similar response is found in human disease, the prolonged duration of action and lack of side effects might make EN101 the standard treatment for myasthenic crises, unstable MG and disease in the elderly, for whom standard treatments are lacking."