Founder of MelTec GmbH and Proteomics Researcher, Walter Schubert of Otto-von-Guericke University Awarded U.S. Patents for Amyotrophic Lateral Sclerosis.

Business Editors/Health/Medical Writers

MAGDEBURG, Germany--(BUSINESS WIRE)--July 16, 2003

Walter Schubert, university educator, founder and partner of MelTec GmbH today announced that he has been awarded three U.S. patents related to Amyotrophic Lateral Sclerosis (ALS). ALS is a devastating neurological disease the cause of which is unknown. It affects the motor neurons of the brain and spinal cord, while leaving the intellect usually completely intact throughout the course of the disease. Apart from a few unconvincing claims of recovery, ALS is a fatal disease, with a mean duration of two to four years. Severe breathing problems occur due to impairment of the respiratory musculature in progressive stages. ALS results in death by choking, posing tremendous disease management problems.

Walter Schubert said that ALS is the cruelest disease he has ever encountered saying, "This is particularly true of the later stages of disease when patients suffer progressively from respiratory insufficiency."

Similarly, in an article on ALS, W.B. Mathiews stated that, "I have never used assisted ventilation by tracheotomy or endotracheal tubes as this only serves in prolonging an intolerable existence. The final stages of which demand the use of morphine (Oxford Textbook of Medicine)." There are no effective therapies capable of stopping the disease available today.

The new patents are based on the already patented MELK technology. Invented by Schubert, this technology allows protein networks to be identified directly in morphologically intact cells and tissues (Schubert, W: Topological proteomics, Toponomics, MELK Technology. In Hecker, M., Mullner, S. (eds). Proteomics of microorganisms: Fundamental aspects and application. Advances of Biochemical Engineering/Biotechnology. Springer Verlag, Berlin-Heidelberg-New York, vol. 83, pp 189-209, 2003). It was while using this technology to investigate the cells of ALS patients that Schubert detected a cell surface protein cluster that is not observed in healthy individuals and that may be involved in abnormal cell-cell contacts between Immune cells and nerve cells. One leading protein within this cluster is the Fcgamma RIII receptor, which is described in the new patents as a target protein for ALS. This receptor mediates the interaction of immune cells with target cells by binding immunoglobulin G1 and G3 subclasses to this cell surface receptor. The patents describe compounds that will block pathogenic interactions between both these cell types and modify or inhibit the abnormal Fcgamma-dependent protein cluster.

Driven by his extensive experience with ALS patients, Schubert's objective has long been to explore ALS, especially using MELK technology. At a meeting of the American ALS Association in Philadelphia two years ago, 30 ALS researchers met to discuss new ways of treating the disease. Considering the dramatic nature of this disease, Schubert used this meeting to inform selected scientists on his findings about the Fcgamma RIII receptor-associated protein cluster in ALS. Meanwhile, American Neurologist Stan Appel (ALS Center, Baylor College of Medicine, Houston, USA) was carrying out experiments with a mouse (knock-out, KO mouse) that lacked Fcgamma receptors. After a series of experiments, it was concluded that this receptor is obviously essential for the ALS-caused damage of nerve cells: the KO mice lacking this receptor failed to develop any changes in the motor neurons after passive immunotransfer of ALS immunoglobulins. Yet the normal mice that express this receptor developed characteristic changes to these nerve cells after immunoglobulin transfer (J. Neurosci. Res., 2002, 69, 110-116). The motor nerve cells constitute precisely the fraction of nerve cell types that enable the movement of muscles and that are selectively affected in ALS.

"These relationships are interesting in several regards," says Schubert. "First, they show that the analysis of the context of many proteins or whole protein families simultaneously in cells using MELK technology has led to correct predictions with regard to the pathogenic significance of the leading protein found. Indeed, this has been confirmed by an independent knock-out experiment that looked into the functional relevance of this receptor protein. Second, they suggest that targeted searching directly in the diseased tissue or altered cells of the patient using MELK can be generalized, that is, extended to other diseases as well. Third, they offer a new approach to the treatment of ALS, not least because the abnormal Fcgamma RIII associated protein cluster, detectable by MELK in the periphery of blood cells, appears to be a biomarker for ALS."

In 2001 Lehmann brothers and Mc Kinsey published a study ("The fruits of genomics") that showed that the present net value per target /NCE program per average pharmaceutical company decreased from 264 m USD in 1995 (classical model) to 34 m USD in 2001 (emerging model), despite the fact that the average number of targets identified by the pharmaceutical industry during this time increased from approximately 50 per year in 1995 to 200 in 2001. The authors concluded that the real driver of this significant economic problem is that target selection. Obviously the present methods (for example "large scale expression profiling") are insufficient to accurately uncover disease-relevant target proteins in cells.

"These difficulties are very likely to be overcome using MELK, as shown by the successful ALS target search," says Schubert.

"Proteins in cells are not stochastically distributed, but rather are spatially highly organized as protein networks," explained Shubert. "Every protein in cells has to be in the right location at the right time and in the right concentration to be able to form a functioning protein network with other proteins functioning under the same rules. These protein networks make the cells work correctly and are therefore of primary interest for understanding function. In networks such as these, proteins are ordered hierarchically in a very strict sense. While some proteins switch a network on and off, other proteins are lower in hierarchy. These modify the function of a network, for example by slowing down or accelerating the interaction of the network proteins.

This essential information concerning the cellular function of the proteins cannot be extracted using 'large scale expression profiling techniques,' because these methods are all based on the disruption of cells and tissues in order to determine the average concentration of proteins in millions of cells."

Schubert is convinced that "Only by reading out the protein hierarchies in cells at the target sites of disease (i.e. in the diseased tissue) directly can specific mechanisms and target proteins be found. Today, MELK technology is the only routinely working instrument available for such analyses on a histological scale from subcellular to supracellular proteome structures (the toponome)."

As far as ALS is concerned, it is essential that every effort is put into exploring the mechanism found to develop a therapy.

To increase cooperation and encourage discussion on MELK technology, Schubert is organizing an international conference between the 24th and 27th of September 2003 in Magdeburg, Germany.

"I am delighted about the contribution to be made to this conference by many distinguished researchers such as Gerd Binnig, the inventor of the scanning tunnelling microscope and cognition network technology. This conference will have a strong focus on how to understand genome function in cancer cells by means of protein analyses in cells using biological and mathematical models.

Walter Schubert, MD

Molecular Pattern Recognition Research Group

Institute of Medical Neurobiology 

ZENIT Building

University of Magdeburg, Germany

Leipziger Strasse 44

39120 Magdeburg, Germany

Tel ++49-171-3217053

Email: [e-mail]