Studies identify nephrin as a key target for therapeutic strategies to improve kidney function
Research Triangle Park, N.C. -- July 6, 1999 -- BioStratum Incorporated announced today the publication in the journal Proceedings of the National Academy of Sciences (volume 96, pages 7962-7967) of the paper entitled "Nephrin is specifically located at the slit diaphragm of the glomerular podocyte". The work was completed in the laboratory of one of BioStratum's founding scientists, Dr. Karl Tryggvason of the Karolinska Institute, Stockholm, Sweden.
In this paper, nephrin is found at the 'slit diaphragm', also referred to as the 'slit membrane', an important structure in the kidney's filtration barrier. Nephrin appears to form a 'zipper-like' filtration structure that functions both as a key structural motif which organizes and maintains the integrity of the filtration barrier as well as a porous filtration structure that allows the liquid portion of the blood to pass but not plasma proteins.
A break-down in the kidney's ability to filter proteins is a common occurrence in most kidney diseases, and results in proteinurea (protein in the urine). Proteinuria is not only a consequence of kidney disease, but also is generally regarded as a major contributing factor to the development of end-stage renal disease, a condition requiring renal placement therapy (transplantation, dialysis). Nephrin's key role in the kidney's filtration barrier suggests that treatments which increase the production of this protein or restore its function are likely to improve kidney function by restoring the kidney's ability to filter proteins. BioStratum owns intellectual property rights to nephrin and new treatments based on modulating nephrin function.
This work is especially exciting because until now, very little has been known about how the kidney filters the blood. The present work elegantly depicts (see accompanying images) the location of nephrin at the slit membrane using nephrin specific antibodies that can be detected by electron microscopes. The structural domains of the nephrin molecule suggest a membrane bound receptor that self-associates with a nephrin molecule on a neighboring podocyte cell surface, thus forming a zipper-like connection between the cells, i.e. the slit membrane.
The nephrin gene was originally identified using genetic linkage analysis on patients with a rare disease called congenital nephrotic syndrome, which is a disease characterized by massive proteinuria. The discovery of the nephrin gene was reported last year by Dr. Tryggvason's group in a paper published in Molecular Cell (March 1998, Volume 1, pages 575-582).
"The absence of a functioning nephrin protein has a profound effect on the kidney's filtration barrier. Therapeutic strategies which increase the production of a functional nephrin protein are a promising approach to restore kidney function and arrest proteinuria.", said Dr. Tryggvason. "In support of this strategy are results obtained in our laboratory and other laboratories that demonstrate a correlation between nephrin function and proteinuria in both genetic and acquired kidney diseases."
BioStratum is pursuing several approaches to increase nephrin production including the identification of small molecule drugs that specifically increase nephrin expression, and the application of BioStratum's proprietary Glomerular Gene Transfer Technology. In this approach, a nephrin gene will be transferred into the kidney in order to express a functional nephrin protein to restore the kidney's filtration function. Dr. Tryggvason's group has developed this technology and demonstrated the transfer of functional genes into the kidneys of pigs.
"This advance holds great promise for the development of treatments for a broad range of kidney diseases, which are an enormous medical problem in this country," said Dr. Archie Prestayko, President and CEO of BioStratum. "In fact, the U.S. spends $12 billion annually treating kidney disease, approximately the same amount that it spends treating cancer."
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email: info@biostratum.com
BioStratum Incorporated is a privately held company developing proprietary therapeutics based on recent scientific advances in basal lamina and related technologies. The company's therapeutics are directed against novel basal lamina extracellular targets involved in degenerative and invasive disease processes fundamental to kidney disease, diabetes and cancer. The company has also developed methods for the production of recombinant basal lamina proteins for use in wound repair and advanced tissue regeneration protocols.
Background information on nephrin follows. For more information on BioStratum, go to www.biostratum.com.
Nephrin paper embargoed by PNAS until 5 p.m., EDT, July 5, 1999
Questions and Answers document
1. What is nephrin?
Nephrin is a protein found only in the kidney, and only in the kidney's filtration barrier. It has a key role in maintaining the structural integrity of the filtration barrier, and also in forming a porous filter that prevents proteins from escaping from the blood and into the urine. Nephrin is defective in patients with congenital nephrotic syndrome, a disease characterized by massive amounts of protein in the urine.
2. What happens if nephrin does not function?
If nephrin doesn't function, protein escapes into the urine which results in a condition called proteinuria (protein in the urine).
3. Why is nephrin and proteinuria relevant to kidney diseases?
A break-down in the kidney's ability to filter proteins is a common occurrence in kidney diseases, including diabetic kidney disease, and gives rise to proteinurea (protein in the urine). Proteinuria is generally regarded as a major contributing factor to the development of end stage renal disease, a condition which requires renal replacement therapy (kidney transplant, hemodialysis, or peritoneal dialysis). The identified key role of nephrin in the kidney filtration barrier suggests defects in nephrin's function, whether genetic or acquired through other disease processes, may be the cause of proteinuria in many kidney diseases.
4. Why is nephrin and proteinuria relevant to diabetes?
A common complication of diabetes is diabetic kidney disease, also referred to as diabetic nephropathy, and the first sign of diabetic kidney disease is proteinuria. Diabetic kidney disease is the most common cause of end stage renal disease. Proteinuria is a contributing factor to the progression of diabetic kidney disease, and a major causative factor in the development of diabetic end stage renal disease. No direct link between nephrin and diabetic kidney disease has been established to date, however, scientists suspect that the disease processes of diabetes could be affecting the function of nephrin and thereby resulting in the development of proteinuria.
5. How is knowing nephrin's function useful?
The identified key role of nephrin in the kidney filtration barrier suggests defects in nephrin's function, whether genetic or acquired through other disease processes, may be the cause of proteinuria in many kidney diseases. It therefore suggests that treatments that increase the production of nephrin or restore its function are likely to improve kidney function by restoring the kidney's ability to filter proteins.
6. What is the connection of this work to BioStratum?
The discoverer of nephrin, Dr. Karl Tryggvason, is a Professor at the Karolinska Institute, Stockholm, Sweden, and a principal founder of BioStratum Incorporated. BioStratum owns intellectual property rights to nephrin and new treatments based on modulating nephrin function.
Journal
Proceedings of the National Academy of Sciences