This grant application is in response to PAR-02-049 research objective #5, Vaccine Development. Alzheimer's disease (AD) is a neurodegenerative disorder with catastrophic effects on the elderly population. This disease is poised to approach epidemic proportions; it is estimated that by the year 2025, there will be approximately 22 million cases of AD worldwide, with at least 10 million in the U.S. alone. The need for the development of effective therapies is therefore greater than ever. Investigations of the molecular etiology of this disease have implicated the amyloid-beta (A-beta) peptide as a likely causative factor. The neurotoxic effects of this peptide have long been thought to stem from its oligomerization into insoluble fibrils, which aggregate to form insoluble neuritic plaques. However, recent work indicates that smaller, soluble oligomers may be an additional or, in fact, the true pathogenic culprit. We propose to isolate human single chain Fv (scFv) antibodies that will recognize and bind the A-beta peptide dimer with high specificity and affinity. This will be accomplished by subtractively panning a human scFv library against an immobilized A-beta peptide monomer and dimer, each prepared separately by chemical synthesis and immobilized in a site-isolated fashion. Using this approach, we will produce a human scFv antibody for passive immunization therapy to bind A-beta peptide dimers and abolish their potential to form neurotoxic higher-order oligomers and aggregates.
| Kim, Young Soo; Moss, Jason A; Janda, Kim D (2004) Biological tuning of synthetic tactics in solid-phase synthesis: application to A beta(1-42). J Org Chem 69:7776-8 |
