|
One of the hallmarks of Alzheimer disease (AD) is the formation of amyloid plaques, the chalky deposits found in the brains of AD patients. Inhibiting the formation of these plaques is a significant area of AD research. Élan (NYSE: ELN) and Wyeth (NYSE: WYE) led off anti-amyloid development with a single, but were thrown out at second.
The companies' Betabloc, a highly anticipated anti-amyloid peptide analog, demonstrated biological effects consistent with potential therapeutic utility, but patients suffered serious central nervous system adversities that were probably mediated by the construct's interactions with their immune systems. The clinical trial program was appropriately halted in February.
Even though Betabloc failed to advance in clinical trials, it did demonstrate that amyloid inhibition was a valid avenue of research. Betabloc was only the first of a series of beta amyloid peptide analogs being developed by Élan and Wyeth to block AD brain plaque formation. Moreover, analogs with experimental evidence of a more acceptable immune profile have been developed at various companies and institutions, most notably New York University School of Medicine. One year ago, researchers from New York University School of Medicine indicated that they expect to test an AD vaccine in initial human clinical trials within a year. Certain specific features suggest it and other second-generation analogs will prove safer than Betabloc.
The July 2002 cover story of the journal Developmental Cell is an elegant manuscript that describes well-conceived, painstaking research in model organisms (worms called C. elegans and fruit flies called Drosophila). The paper describes the role of two proteins that play a role in the development of the beta-amyloid constituent of AD plaque.
Scientists at Exelixis (NASDAQ: EXEL) and Pharmacia (NYSE: PFA) discovered that the "aph-1" and "pen-2" proteins are required for presenilin protein activity. Presenilin is mutated in certain families with increased risk of AD, and the presenilin protein may be involved in production of the beta-amyloid.
The content of this manuscript not only reflects well on the genomics-based drug discovery engines of Exelixis and Pharmacia, but also highlights the sophistication required for meaningful scientific discovery. Not only will Exelixis and Pharmacia benefit from specific intellectual property eventually translated into relevant small molecule drugs, but also the industry and academia benefit from further elucidation of this elusive, difficult-to-target, complex signaling pathway.
The discovery of aph-1 and pen-2 are only the first step in the development of new AD drug targets. Complicated biochemical pathways do not lead to rapid translational development. Perhaps aph-1 and pen-2 hold the key to further biological pathway elucidation. Perhaps it is the protein "nicastrin, " recently shown to be required for gamma secretase activity. Perhaps the best AD target is still undiscovered. As the biochemical pathways that lead to AD are worked out, novel compounds impacting specific proteins in those pathways will enter clinical trials. The failure of Betabloc is part of the process of testing and refining compounds that target fundamental proteins in disease.
[Btech News]
««« »»»
Last Revised at December 10, 2007 by Lusine Kazoyan, M.D.
|
