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INHIBITORS OF ALZHEIMER'S DISEASE AMYLOIDOSIS

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44AG017787-02
Agency Tracking Number: AG017787
Amount: $0.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: N/A
Solicitation Number: N/A
Timeline
Solicitation Year: N/A
Award Year: 2002
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
PROTEOTECH, INC. 12026 115TH AVE NE
KIRKLAND, WA 98034
United States
DUNS: N/A
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 GERARDO CASTILLO
 (425) 823-0400
 CASTILLO@PROTEOTECH.COM
Business Contact
 DENNIS MCCURLEY
Phone: (425) 823-0400
Email: MCCURLEY@PROTEOTECH.COM
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, judgment and emotional stability that gradually leads to
profound mental deterioration and ultimately death. AD is the leading cause of
dementia in the elderly, today affecting 4-5 million American, which is
expected to double in incidence in the next 25 years. AD is characterized by
the brain accumulation of insoluble fibrillar amyloid deposits containing the
beta-amyloid protein (ABeta), either as extracellular amyloid plaques in the
brain parenchyma or in blood vessel walls. AB 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 has become
a central target for the development of new drugs for the treatment of AD and
years of disease onset.
Our Phase I SBIR studies demonstrated that the basement membrane protein
laminin acts as a potent inhibitor of AB fibril formation, both in vitro and in
vivo. Following elastase digestion and sequencing, an AB-binding site on
laminin was localized to the C-terminal globular domain repeats on the laminin
Al chain, within a 55-kDa region. A 12 amino acid peptide was futher identified
within the 4th globular domain of laminin Al to be a potent inhibitor of ABeta
fibrillogenesis. Following the screening of over 300 overlapping 12-14 amino
acid peptides of various laminin alpha-chain globular domains, we identified
six ideal peptide candidates (each 12-13 amino acids in length) that were found
to be potent inhibitors of ABeta amyloid fibril formation, and which cause a
disruption of pre-formed AD amyloid fibrils. Based on these promising results,
Phase II SBIR studies will involve the synthesis of related peptide analogs
(i.e. D-amino acids, smaller truncated peptides) derived from the six parent
form laminin globular domain-derived peptides with the goal of optimizing new
peptides that have the ability to 1) inhibit All fibril formation and
disrupt/disassemble preformed All fibrils, 2) inhibit All-induced toxicity, 3)
resist rapid bio-degradation, 4) cross the blood-brain barrier, and 5) retard
or reverse AD-like amyloid plaque pathology in a transgenic mouse model of AD.
These studies are anticipated to lead to the identification of a new peptide
candidate for the treatment of All amyloidosis in AD and related disorders.

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

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