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Novel Approach to Treat Alzheimer's and Other Diseases Offered by Targeting Cell Membrane RAFTS JADO Technologies' Scientists and Collaborators Publish Study in Science


4/25/2008 7:19:30 AM

DRESDEN, Germany, April 25 /PRNewswire/ -- JADO Technologies GmbH, the leading developer of RAFT intervention therapeutics, announced today the publication of a paper in Science demonstrating a potential novel strategy for therapeutic intervention in Alzheimer's and other diseases by targeting discrete sub-compartments in the cell membrane (RAFTS). The study conducted by JADO scientists together with several academic collaborators will appear in the April 25, 2008 issue of the magazine.

Entitled "Efficient inhibition of the Alzheimer's disease Beta-secretase by membrane targeting", the paper describes how Beta-secretase, the rate-limiting enzyme in the production of Alzheimer's disease associated Beta-amyloid peptide, can be inhibited effectively using compounds anchored to cell membrane RAFTS. Unlike existing approaches for Beta-secretase inhibition that do not account for the intracellular location of the target protein or the different conformation that the protein may assume in this context, these RAFT inhibitors are delivered to the exact site where Beta-secretase executes its neurotoxic activity.

"Our data provide proof-of principle of a new approach for directing small molecule inhibitors to disease causing RAFT targets in cellular membranes. In this instance, by directing inhibition to the sub-compartment where the enzyme is active, the approach has potential to be used in the design of more effective Beta-secretase inhibitors for the treatment of Alzheimer's disease," noted Professor Kai Simons, Max-Planck Institute of Molecular Cell Biology and Genetics and co-founder of JADO. "We believe that this novel strategy can be used to design therapeutics against other RAFT targets in a range of other diseases."

Beta-secretase is internalized from the cell membrane into intracellular compartments (endosomes) where it cleaves its substrate, Amyloid Precursor Protein (APP). Most soluble inhibitors of Beta-secretase do not gain access to this internal location, so the researchers first tested whether anchoring of such a Beta-secretase inhibitor to the membrane would confer inhibitory activity upon it by bringing it to the right compartment. A peptide inhibitor of Beta-secretase, which inhibited soluble ss-secretase but failed to block the enzyme in a cellular assay, was coupled to a sterol anchor molecule and a potent inhibition of Beta-secretase activity demonstrated. Concentrations as low as 100 nM of the anchored inhibitor were sufficient to completely block appearance of amyloid peptide. In an animal model of Alzheimer's disease, the same sterol-coupled inhibitor reduced Beta-amyloid formation in the brain by 50% over 4 hours, whereas the free inhibitor was ineffective.

The researchers explained that the advantage of using a sterol anchor was to target and increase the concentration of the inhibitor in the sterol-rich RAFT domains where Beta-secretase cleaves APP. Evidence was also provided that the RAFT anchor could not be substituted by any other lipid type and that knowledge of RAFT chemistry is crucial.

"This seminal paper is the culmination of many years pioneering research by this team in the emerging field of RAFT intervention therapeutics. At JADO we have taken this approach to the next level and are building a pipeline of compounds targeting RAFTS for the treatment of allergic disorders and infectious diseases. Alzheimer's disease has historically been an area of research for our company founders. This data supports our belief that the RAFT approach also has potential in a diverse number of indications," said Charl van Zyl, CEO of JADO.

The authors of the paper are: Lawrence Rajendran(1), Anja Schneider(4), Georg Schlechtingen(2,6), Sebastian Weidlich(2), Jonas Ries(3), Tobias Braxmeier(2,6), Petra Schwille(3), Jörg B. Schulz(5), Cornelia Schroeder(6), Mikael Simons4, Gary Jennings(6), Hans-Joachim Knölker(2,6), Kai Simons(1,7)

(1)Max-Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307, Dresden, Germany;

(2)Department of Chemistry, Technical University of Dresden, Bergstr. 66, 01069 Dresden, Germany;

(3)Biotec, Biotechnologisches Zentrum, Tatzberg 47/49, Dresden, 01307 Germany;

(4)Max-Planck Institute for Experimental Medicine, 37075, Göttingen Germany;

RAFTS are discrete sub-compartments in the lipid membrane of cells that play a central role in complex physiological processes, such as the immune response and in many pathological situations. In infectious diseases, RAFTS are hijacked by pathogens to gain entry into cells. By blocking RAFT processes, JADO is pursuing the development of new therapeutics with a novel mode-of-action.

About JADO Technologies JADO is a leader in the emerging field of RAFT intervention therapeutics. Representing a paradigm shift in drug development, RAFT therapeutics have the potential to address multiple unmet needs, particularly in allergy, infectious diseases, Alzheimer's disease and cancer.

RAFTS are sub-compartments of cell membranes that play an integral role in key biological pathways. The Company's RAFT Intervention Technology(R) provides a unique platform, protected by a strong patent position, to drive significant pipeline development opportunities. JADO has leveraged its technology to generate multiple small molecule drug candidates, with its lead program in Phase IIa clinical trials for allergy indications. The Company is supported by a global network of clinical and academic experts, including JADO founders, Prof. Kai Simons, Prof. Marino Zerial, Dr. Teymuras Kurzchalia (Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden) and Prof. Hans-Joachim Knolker (Technical University of Dresden). JADO is headquartered in Dresden, Germany with a subsidiary in Bethlehem, Pennsylvania (USA). For more information, please visit our website: http://www.jado-tech.com.

CONTACT: Contacts: JADO Technologies, Charl van Zyl, CEO,
+49(0)351-796-3800; Halsin Partners, Mike Sinclair, Director,
+44(0)20-7084-5955



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