Cleavage
of APP to generate Aß requires a minimum of two active secretases. The first
cleavage is carried out by the aspartyl protease
ß-secretase (BACE1), which
cleaves APP in its
extracellular portion to generate the soluble APP. This leaves behind the
carboxy-terminal
section of APP (APP C99), which includes its transmembrane and cytoplasmic
regions. C99 then
becomes a substrate for the protease gamma-secretase, which consists of a
complex of at least
four proteins. Recently published studies indicate that nicastrin, one member
of the gammasecretase
complex, mediates the docking of APP to the active site of the complex.
Cleavage by
gamma-secretase generates two fragments of Aß (1-40 and 1-42), one of which
is toxic Aß (1-42). Numerous groups have focused their attention on developing therapeutics
that will reduce
Aß levels based on these findings.
The principle of the RemeGenix therapeutic approach is centered on BRI-2, a
membrane
localized protein that is known to bind to APP. The company has demonstrated
that BRI-2
functions as a competitor for nicastrin in its interaction with the APP,
inhibiting its interaction
with gamma-secretase and the generation of Aß. The inhibitory activity of
BRI-2 on APP
processing has been mapped to a small sub-sequence of the full-length BRI2
protein. This
provided the company with several specific peptides with therapeutic
potential for the
treatment of AD. The company proposes to develop peptide mimetics of BRI-2 as
drugs to
inhibit gamma-secretase and reduce the production of Aß.