BioStratum Announces Novel Post-Amadori Inhibitor Drug Candidates for Diabetes Complications
-- New Inhibitors Target Different Step in Nonenzymatic Glycation Pathway --

Lake Forest, IL, and Research Triangle Park, NC, March 4, 1997 -- BioStratum Incorporated today announced the in vitro identification of novel post-Amadori inhibitor drug candidates for the prevention of diabetic complications. BioStratum collaborators published these findings in the current issue of the Journal of Biological Chemistry (vol. 272, pgs. 5430-5437). In follow-up studies, one of these drug candidates has been shown to inhibit the development of nephropathy in animal models of diabetic complications.

According to the Diabetes Control and Complications Trial (DCCT) findings, diabetic complications such as nephropathy, retinopathy, and neuropathy correlate in most cases with the severity of hyperglycemia experienced by the diabetic patient. An important mechanism by which hyperglycemia can cause such complications is through increased nonenzymatic glycation of proteins, nucleic acids, and lipids. This chemical reaction can alter the structure and function of these biomolecules, which can have damaging effects on tissues and organs. This process begins with the nonenzymatic reaction of glucose with biomolecules and proceeds through an Amadori intermediate, which irreversibly converts to Advanced Glycation End-Products (AGEs) that are believed to be a major causative factor in the pathogenesis of diabetic complications. Approximately 30 percent to 40 percent of insulin dependent (type I) diabetics develop nephropathy, which is the leading cause of end-stage renal failure and is estimated to cost the U.S. healthcare system $6 billion annually.

Prior to the current study, this same group of BioStratum collaborators reported the development of a new method
to prepare and stabilize Amadori-rich protein intermediates for studies of their conversion to AGE products. The formation of AGEs through protein Amadori intermediates is considered a major pathway for in vivo AGE formation. In the current work, the researchers utilize these intermediates in a rapid in vitro screening method to identify compounds that inhibit the irreversible conversion of Amadori intermediates to AGEs. Several compounds were found to exhibit post-Amadori inhibitory activity, including pyridoxamine, a derivative of vitamin B6. The well-studied AGE inhibitor aminoguanidine exhibited very little post-Amadori inhibitory activity. In subsequent preclinical studies, oral administrations of pyridoxamine inhibited the development of nephropathy in animal models of diabetic complications.

According to the senior co-author of this work, Dr. Billy G. Hudson, Professor and Chair of the Department of Biochemistry and Molecular Biology at the University of Kansas Medical Center, "By effectively targeting a different step of the glycation pathway, post-Amadori inhibitors may also complement the use of other AGE inhibitors that target different mechanisms of AGE formation."

Dr. John Baynes, Carolina Distinguished Professor of Chemistry and Biochemistry at the University of South Carolina, and a leading expert in this field who serves as a scientific advisor to BioStratum, added that "Compounds that inhibit AGE formation through this mechanism have the potential to also modulate oxidative damage from lipid-associated glycoxidation reactions that may contribute to diabetic complications, including atherosclerosis.

"Although a correlation does exist between the degree of hyperglycemia and the severity of diabetic complications, recent epidemiology studies suggest that the propensity for certain diabetics to develop diabetic nephropathy is genetically linked, with one or two genes suspected. BioStratum is sponsoring ongoing research in the laboratory of Dr. Karl Tryggvason, Professor of Medical Chemistry at the Karolinska Institute, Stockholm, Sweden, to identify such susceptibility genes in humans through genetic linkage analysis using samples from families in Finland and the United States with prevalent diabetic nephropathy.

"The identification of such susceptibility genes could lead to a DNA-based test to determine a diabetic's susceptibility to develop kidney disease, which will greatly assist in the clinical management of such patients," said Dr. Tryggvason. "In addition, the identification of the gene or genes and the proteins they may encode will provide researchers with the identity of biochemical pathways and targets that may play a significant role in the disease process, pointing the way for new therapeutic approaches."

BioStratum Incorporated, based in Lake Forest, Illinois, and Research Triangle Park, North Carolina, is a privately held biotechnology company developing a new class of proprietary therapeutics based on recent scientific advances in basal lamina technology. The Company's therapeutics are directed against novel basal lamina extracellular molecular targets involved in invasive and degenerative disease processes fundamental to a broad range of deadly and debilitating diseases. BioStratum's ongoing preclinical studies include the evaluation of the Company's proprietary therapeutics against tumor metastasis, tumor angiogenesis, complications of diabetes, kidney diseases, autoimmune diseases, and AIDS. The Company is also developing methods for the production of recombinant basal lamina for use in advanced, ex vivo cell therapy and tissue regeneration protocols.