BioWorld International Correspondent

The University of Copenhagen in Denmark is coordinating a €9.7 million pan-European research consortium that aims to find new central nervous system drug leads based on the biology of the neural cell adhesion molecule (NCAM), a receptor protein involved in brain development and control of memory and learning.

Elisabeth Bock, head of the protein laboratory at the university's Panum Institute, who discovered NCAM in the 1970s, is heading up the European Union-funded project, called Promemoria. The consortium comprises 18 organizations, including 14 academic research groups and four biotechnology firms. Those are Copenhagen-based Enkam Pharmaceuticals A/S, of which Bock is scientific founder; Reglia AB, of Gothenburg, Sweden; Schaefer-N A/S, of Copenhagen; and Neuropharma SA, a subsidiary of Zeltia Group, of Madrid, Spain.

"NCAM is not new, it's just that it has been so inaccessible to study," Bock told BioWorld International. Many of its effects are mediated when two NCAMs on adjoining neurons bind. Bock and her team have developed small-molecule probes that can trigger the same events.

The protein is produced in several isoforms, and alterations in its glycosylation pattern also influence its activity. Promemoria has a four-year plan, which includes atomic level structure-activity relationship studies of NCAM, physiological studies of the influence of NCAM on neuronal cell membrane function and on cell growth and survival, and in vivo studies with animal models. The effects of NCAM on animal behavior are wide-ranging and dramatic. "If you have a knockout mouse where NCAM is not expressed, you have some very stupid and aggressive animals," Bock said.

Her research group recently showed that a 15-amino-acid peptide mimetic of the NCAM binding site for fibroblast growth factor receptor (FGFR) 1 conferred a long-term improvement on rat memory. The data were published in the April 2004 issue of the Journal of Neuroscience.

The same principle underpins Enkam's lead drug candidate, FGLL, which is due to enter a Phase I/II trial in the third quarter in patients with either mild Alzheimer's disease or mild cognitive impairment. The molecule, also derived from the NCAM FGFR binding site, had multiple effects on a rat model, Enkam CEO Morten Albrechtsen told BioWorld International. The company will probably seek a deal after the study.

"We are in discussions with a number of [potential] partners now," he said.

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