Gene Delivery and Gene Therapy for Alzheimer’s Disease - Gene Delivery and Therapy for Neurological Disorders - page 95

For example, convection-enhanced delivery (CED) is a method
developed specifi cally for CNS delivery of large compounds that
are not BBB-permeable, in which a constant pressure gradient is
applied to the infusate to cause bulk fl ow, rather than diffusion,
through the interstitium [ 70 , 71 ]. Step cannulae may also be used
for injection, which prevent refl ux into the track of injection [ 72 ].
If a study is designed for widespread delivery to the CNS, thera-
peutic genes may be delivered via intracerebroventricular or periph-
eral methods. AAV9, as it is BBB-permeable, may be delivered
intravenously in the periphery, avoiding the potential hazards and
diffi culties of intracranial injection. However, adult animals may
show a low neuronal versus glial transduction effi ciency with AAV9,
and signifi cant amounts of peripheral tissue may be transduced
when vector is delivered peripherally [ 41 ]. Other delivery methods
include targeting brain areas via retrograde transport from muscle
to spinal neurons [ 73 ]. In certain diseases or disease states, such as
stroke, timing of therapy may be crucial for outcome. In AD or
other slowly progressing neurodegenerative diseases, therapy may
be effective at multiple disease stages.

1.5 Animal Models
of Alzheimer's Disease

The use of transgenic mouse models that recapitulate behavioral
and pathological aspects of AD has proven an invaluable tool for
studying the disease etiology and effectiveness of therapeutics. AD,
the most prevalent neurodegenerative disorder in the world, is
characterized by amyloid- ) plaques and neurofi brillary tan-

gles, which are thought to cause toxicity responsible for synapse
loss and neurodegeneration leading to defi cits in memory and cog-
nitive function. A

ʲ (A ʲ

immunotherapies, which have been the main
focus of therapeutic development, have shown improvements in
amyloid clearance and spatial learning in mouse models expressing
mutant APP [ 74 , 75 ], but these benefi ts have not yet translated to
humans in clinical trials. Recently, a phase III trial of Solanezumab,
Eli Lilly and Company's humanized monoclonal A

ʲ

antibody,
reveals small but signifi cant improvements in cognition in mild AD
patients [ 76 ]. However, these changes are very small and require
further analyses.
Despite the disappointing lack of translation of effect from
mice to humans of A

ʲ

antibody therapies, animal models remain
useful for easily exploring many features of the disease and the
extent to which genetic insults affect disease. The fi rst report of a
transgenic mouse displaying AD pathology was that of the PDAPP
mouse in 1995, which overexpresses mutant A

ʲ

ʲ precursor protein

(APP) leading to A plaque deposition in relevant brain areas [ 77 ].

Tg2576, another line expressing APP Swedish (APPSwe) mutant
developed soon after, shows similar pathology as well as age-related
cognitive decline [ 78 ]. Transgenic mice expressing familial
AD-linked mutants of APP and presenilin-1 (PS1) (APP/PS1
mice) have also proven valuable tools in AD investigations, as

ʲ