Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 69

the full-length human protein) levels 3 days postinoculation [ 123 ].
In order to achieve stable gene replacement, this group then gen-
erated an HSV/adeno-associated virus (AAV) hybrid amplicon,
carrying the expression cassette for the ATM and EGFP cDNA,
fl anked by AAV inverted terminal repeats (ITRs). This hybrid
vector, in the presence of AAV Rep proteins, mediated site-specifi c
integration of the transgenic sequences into the AAV1 site of chro-
mosome 19 in human cells and in Atm −/− mice carrying that human
locus. The functional activity of the vector-derived ATM was con-
fi rmed in vivo by ATM autophosphorylation. Hence, HSV/AAV
hybrid amplicon vectors are able to mediate functional targeted
integration of the ATM cDNA into cultured AT cells and in Atm −/−
mice in vivo [ 124 ].

14.2 Neurodege-
nerative Diseases

One of the most studied neurodegenerative disease is Alzheimer's
disease (AD). In this pathology, it is believed that a peptide known
as A

(amyloid beta), acts as a neurotoxin that produces neurode-
generation. More precisely, a recently enunciated hypothesis states
that soluble oligomers of A

β

-derived
diffusible ligands) bind to postsynapses, and that this binding
would be responsible for triggering toxic effects that ultimately
lead to neuronal death [ 125 , 126 ]. A

β peptide (named ADDLs: A β

peptide is generated by
degradation of amyloid precursor protein (APP). Under physio-
logical conditions, APP is fi rst cleaved by an

β

-secretase, resulting
in a nonamyloidogenic soluble peptide. However, under abnormal
conditions or by blocking the normal degradation pathway, APP is
cleaved by the

α

-secretase BACE-1, generating an amyloidogenic
peptide of 40-42 amino acids [ 127 ]. A

β

initially aggregates in
soluble oligomers of 2-14 monomers (ADDLs), which can bind to
the postsynaptic densities from very early stages and then form the
typical amyloid plaques [ 126 , 128 - 132 ].
Two studies describe the use of amplicons for A

β

vaccination in
mice, as a possible therapeutic strategy for AD, aimed at preventing
A

β

fi brillogenesis and/or to enhance removal of parenchymal amy-
loid deposits. In the fi rst study, the amplicons expressed either A

β

β

1-42 (HSVA 1-42 fused to the molecular adjuvant tetanus

toxin Fragment C (HSVA

β ) or A β

/TtxFC). Peripheral administration of
both vaccines augmented humoral responses to A

β

β and reduced

CNS A β deposition in transgenic Tg2576 mice. However, HSVA β

vaccination was found to be toxic, inducing expression of proinfl am-
matory transcripts within the mouse hippocampus [ 133 ]. A second
amplicon vector was then constructed [HSV(IE)A

β (CMV)IL-4]

that codelivers A 1-42 and interleukin 4 (IL-4), a cytokine that

promotes the generation of Th2-like T-cell responses. Triple trans-
genic AD (3XTg-AD) mice, which progressively develop both amy-
loid and neurofi brillary tangle pathology, were vaccinated with
these amplicons. Increased Th2-related A

β

-specifi c antibodies
improved learning and memory, while prevention of AD-related

β