Gene Delivery and Gene Therapy for Alzheimer’s Disease - Gene Delivery and Therapy for Neurological Disorders - page 90

now known to be more prevalent than AAV1-neutralizing
antibodies in human [ 37 ]. Thus, since tropism is determined by
the cap genes, rAAV has been developed with AAV2 ITRs and rep
and cap genes of alternative serotypes, thereby avoiding actions of
AAV2-neutralizing antibodies. AAV2 ITRs are used because AAV2
is the most understood serotype, in terms of host cell response as
well as biochemical and genetic properties; transcapsidation with
alternate serotype capsids has expanded the utility of this proto-
typical vector.
By packaging the capsids of different serotypes with AAV2
ITRs, the transduction effi ciencies of naturally occurring AAV sero-
type vectors in different tissues and cell types have been compared,
providing a vast amount of information on specifi c serotypes in the
literature. Keeping in mind inter-study variation in AAV promoters,
transgenes, titers, and doses, comparative effi ciency of transduction
in major tissues has been established ( see Table 1 for summary)
[ 30 , 38 ]. AAV2 transduces a wide range of cell types and tissues
with moderate effi ciency (the liver, muscle, lung, CNS). AAV9 has
a similar profi le to AAV2 but shows more effi cient transduction
[ 39 ]. In skeletal muscle, AAV1 and AAV7 show rapid onset and
high transduction levels [ 39 ]. AAV6, because it differs from AAV1
by only six amino acids, also transduces skeletal muscle well.
In the nervous system, AAV1, 2, 5, 8, and 9 have been the
most widely studied serotypes, with AAV1 and 5 conferring a supe-
rior transduction effi ciency than AAV2, and AAV8 and 9 confer-
ring further superior transduction over AAV1 and 5 in the rodent
CNS [ 30 , 32 , 34 , 40 , 41 ]. In comparison to AAV2, most serotypes
show greater CNS transduction in terms of total transduced brain
volume and total number of transduced cells, but also in some
cases, higher level of gene expression per cell [ 32 , 40 ]. Burger
et al. assess CNS transduction of AAV1, 2, and 5 capsids fl anked
with AAV2 ITRs injected into different regions of the rat brain
[ 32 ]. While all constructs primarily transduced neurons, AAV1 and
AAV5 capsids show higher transduction effi ciency than AAV2 in all
CNS regions, including the hippocampus, striatum, globus palli-
dus, substantia nigra, and spinal cord. In the hippocampus, AAV1
and 5 capsids mostly transduce pyramidal neurons in CA1-CA3
regions, while AAV2 mostly transduces neurons in the hilar region
of the dentate gyrus. AAV8 shows superior transduction to AAV1,
2, and 5 in the hippocampus of the rat brain, although one study
shows that an effi cient gene transfer of AAV8 causes neurotoxic
green fl uorescent protein (GFP) expression levels [ 40 ]. In contrast
to rodent fi ndings, a study in adult cynomolgus monkeys shows
superior transduction by AAV1 and AAV5 compared to AAV8 in
the striatum [ 42 ]. Klein et al. showed that AAV9 conferred more
effi cient gene transfer in the brain than AAV2 or AAV8 in rat
tauopathy models [ 34 ]. For AD studies, researchers may be inter-