Gene Delivery and Gene Therapy for Alzheimer’s Disease - Gene Delivery and Therapy for Neurological Disorders - page 87

For the treatment of Alzheimer's disease (AD) by gene therapy,
optimization of transduction effi ciency and specifi city is important
for targeting affected brain areas. Despite being the most prevalent
neurodegenerative disease worldwide, there are still no effective
treatments for AD, which is characterized by accumulation of
intracellular microtubule-binding protein tau (map-tau) and extra-
cellular beta-amyloid (A ) plaques thought to lead to synaptic

degeneration and progressive cognitive impairment. This pathol-
ogy in the AD brain starts in the entorhinal cortex and spreads to
hippocampal subregions and cortical areas [ 29 ].
One fundamental aspect of AAV specifi city for targeting of rel-
evant cell types and brain areas is AAV serology. There are at least
100 known AAV serotypes of which about 12 have been developed
into a vector. AAV serotypes are classifi ed based on their cell sur-
face antigens in the capsid protein motifs (Table 1 ). A “new” sero-
type is defi ned as one that does not cross-react with neutralizing
sera that are specifi c for already-existing serotypes; based on this
defi nition, AAV6 is not a true serotype because the serology of
AAV6 is nearly identical to that of AAV1 [ 30 ]. AAV2 is the fi rst
serotype to be cloned into bacterial plasmids [ 31 ] and has since
been widely used. The following discovery and study of other sero-
types has highlighted not only their ability to evade naturally
occurring human AAV2-neutralizing antibodies but also their abil-
ity for increased CNS gene transfer as compared to AAV2 both in
terms of total transduced brain volume and total number of trans-
duced cells [ 32 - 34 ]. Because the capsid motif governs the way
AAV enters the host cell, each serotype has a unique transduction
effi cacy, and this can be taken advantage of by researchers for infec-
tion of particular cell types or tissues using naturally occurring
serotypes as well as for design of hybrid serotypes for tissue or cell-
specifi c targeting.
AAV hybrid serotypes have capsid protein modifi cations that
increase the specifi city, effi ciency, and effi cacy of viral infection (for
review, see ref. 35 ), which are essential for targeting the tissue and
cell type of interest and minimizing dose. One variety of hybrid
serotype is obtained through transcapsidation, or packaging the
genome containing ITRs ( cis -acting) from one serotype into the
capsid of a different serotype ( trans -acting virion shell). The tro-
pism, or host cell specifi city, is determined by the three cap genes;
tropism of an AAV vector during transduction can thus be changed
by exchanging the rep/cap gene source. Most vectors that were
developed prior to the development of hybrid vectors have been
AAV2, and these are most used as ITRs for cross-packaging in cap-
sids of another serotype. Transcapsidation of the AAV2 genome
allows the genome from this well-characterized serotype to target
cell types that don't express receptors utilized by AAV2. AAV2 is
present in ~80-90 % of the population; AAV2-neutralizing anti-
bodies were found in humans in early AAV studies [ 36 ] and are

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