Viral Vectors in Primate Research: Examples from Parkinson’s Disease Research - Viral Vector Approaches in Neurobiology and Brain Diseases - page 324

effi cacy in an open-label phase I clinical trial [ 7 ]. Very recent news,
not yet peer-reviewed however, state that AAV2-neurturin did not
modify disease course and severity in a phase II trial.
Another putative candidate in the development and maintain-
ing of LID process is the transcription factor, FosB, whose stria-

tal expression was correlated with the severity of dyskinesia in
parkinsonian macaques treated with L -DOPA [ 41 ]. In this study,
viral overexpression of AAV2-

Δ

FosB did not alter dyskinesia sever-
ity in animals previously rendered dyskinetic, whereas the overex-
pression of

Δ

JunD dramatically dropped the severity of this side
effect of L -DOPA, without altering the antiparkinsonian activity of
the treatment.
Against the backdrop of ongoing clinical trials using AAV2
vectors for gene therapy, several recent studies evaluating the trans-
duction effi ciency of different AAV serotypes in the primate brain
have been reported. AAV1, AAV5, and AAV8 are of particular
interest because of their favorable properties of transduction pat-
terns in the basal ganglia [ 42 - 44 ]. Brain infusion of AAV1 and
AAV5 vectors results in expression mostly neuronal [ 45 - 47 ] and
appears to be more effi cacious than AAV2 in transduction, at least
in the substantia nigra and striatum [ 48 ]. AAV1 and AAV5 are also
superior to AAV8 in transducing striatal neurons in adult cynomol-
gus monkey [ 46 , 49 ] and therefore better candidates for targeting
this structure in possible therapeutic applications. Parkin gene
therapy in rhesus macaques overexpressing

Δ

-synuclein was also
investigated with AAV1 serotype [ 50 ]. However, this study not
only did not report any protective effect of Parkin against the
α

α

-synuclein-induced loss of dopaminergic neurons in the SNpc but
also was limited by a partial transduction of neurons.
Interestingly, the AAV serotype that has triggered considerable
attention in the last 5 years is the AAV9, which displays a striking
ability to cross the blood-brain barrier [ 51 , 52 ]. Intravenous
administration of AAV9-GFP vectors to mice [ 53 ] or cat [ 54 ]
effectively crossed the blood-brain barrier and transduced cells
throughout the brain. In this context, AAV9 therapy has recently
led to proof-of-concept preclinical rescues in mouse models of spi-
nal muscular atrophy disease [ 55 , 56 ] and of a lysosomal storage
disorder [ 57 ]. Consistent with adult mice [ 53 , 58 ], the CNS trans-
duction was mainly in glial cells after intravascular administration
to adult monkeys [ 59 , 60 ]. Thus, the neuronal transduction in
neonates is a useful tool as ability to transfect brain decreases over
time, being high at P1 and decreasing dramatically by P10 already
[ 56 ]. This last result suggests a critical developmental period in
which AAV9 transfection has maximal effi cacy. Further, it has been
recently reported that AAV9 injected intravenously in newborn
rhesus macaques leads in effi cient, exclusively neuronal and wide-
spread transduction of the brain paving the way to large-scale
genetic modeling of brain diseases in the rhesus macaque [ 61 ].
Similarly, intravenous AAV9 delivery to fetal macaques [ 62 ] has