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Laminin-Derived Protein Fragments as Inhibitors of Alzheimer's Amyloidosis

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44AG017787-05
Agency Tracking Number: AG017787
Amount: $2,288,170.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: N/A
Solicitation Number: PHS2006-2
Timeline
Solicitation Year: 2006
Award Year: 2006
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
12026 115TH AVE N.E.
KIRKLAND, WA 98034
United States
DUNS: N/A
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 ALAN SNOW
 (425) 823-6364
 snow@proteotech.com
Business Contact
 DENNIS MCCURLEY
Phone: (425) 823-0400
Research Institution
N/A
Abstract

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, and judgment that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly and is characterized by the brain accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (Abeta). Abeta amyloid formation, deposition and persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction, and therefore is a central target for the development of new therapeutics for the treatment of AD and related disorders. Our previous Phase I studies first identified a new and relevant Abeta binding site on laminin localized to the globular domain repeats on the laminin A chain. Over 300 overlapping 12-13mer peptides spanning the binding site area were synthesized and tested using a varietry of in vitro screening methods to determine the best 12-13mer peptides demonstrating the most potent anti-Abeta amyloid inhibitory/disruptive activity. In Phase II studies, we assessed the top six 12-13mer peptides and designed, synthesized, tested and identified smaller 6-9mer peptide analogs that served as lead pre-clinical candidates. These rigorous studies have now led to the identification of two novel small 7mer D-amino acid peptides that following peripheral administration in a relevant APP transgenic plaque producing animal model of AD cause a marked reduction and clearance of brain Abeta amyloid load (by 50-70%), and improved memory (by 28-44%). This Phase II SBIR continuation proposal project will now further develop these two novel 7mer pre- clinical candidate peptides in vitro and in vivo to determine their pharmakokinetic, blood-brain-barrier permeability, and toxicity profiles. Best route of administration (i.e. nasal, i.v. and/or s.c.), dosage and time- dependent efficacy for reduction and clearance of brain Abeta amyloid and improved memory will also be further determined in the APP transgenic plaque-producing mouse model that demonstrates memory deficits with increased Abeta burden. These studies will help us select a novel small peptide pre-clinical candidate (and its backup) that will be developed for human clinical trials and commercialization, and that has the promise to serve as an exciting new treatment for AD and related Abeta amyloidosis.

* Information listed above is at the time of submission. *

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