Viral Vectors in Primate Research: Examples from Parkinson’s Disease Research - Viral Vector Approaches in Neurobiology and Brain Diseases - page 323

3 Adeno-Associated Virus Vectors

Besides the above data for LVs, the majority of current gene ther-
apy approaches for the treatment of CNS disorders have focused
on the use of AAV vectors, as they offer stable, effi cient transduc-
tion and durable expression of neurons. There are currently more
than 100 AAV serotypes described [ 24 , 25 ] differing mainly by the
amino acid composition of the capsid proteins, which dictates
receptor/tissue specifi city [ 26 - 28 ]. Among those, 12 different
AAV serotypes have been engineered into recombinant viral vec-
tors for gene therapy applications. To date, the most widely AAV
serotype used both experimentally and clinically to deliver genes to
the CNS is AAV2, which demonstrates safety and long-term effec-
tive gene transfer in the CNS and especially in basal ganglia. AAV2
vectors have been designed to deliver the cDNA encoding AADC
in the striatum of MPTP-treated monkeys [ 29 ]. Transduced with
this vector, striatal neurons gain the ability to convert the adminis-
tered L -DOPA into dopamine. Striatal injection of this AAV2 con-
struct has shown clinical improvement in parkinsonian monkeys
continues for at least 8 years with AAV2 vectors [ 30 - 32 ].
Remarkable effi cacy has been also observed in the same model
when all three dopamine-synthesizing enzyme genes (TH, AADC,
and GCH) transduced with AAV2 are coexpressed in the striatum
with restoration of motor functions [ 33 ].
Besides normalizing dopamine levels and based on the clinical
success of modulating the subthamic nucleus (STN) activity fol-
lowing deep brain stimulation [ 34 ], a gene therapy approach was
proposed to phenoconvert excitatory STN projections into inhibi-
tory projections for silencing its pathologic output. Gene encoding
glutamic acid decarboxylase (GAD), the rate-limiting enzyme for
the synthesis of GABA, was delivered using an AAV2 vector to tar-
get the glutamatergic neurons of the STN in MPTP-treated rhesus
monkeys [ 35 ]. This therapy affected the course of MPTP-induced
motor signs as refl ected in the relative improvement of the clinical
rating scores. However, the improvements obtained after several
clinical trials have been so far modest compared with DBS [ 36 , 37 ].
Like lentivirus vector, AAV2 expressing neurotrophic factors
could be used as a neuroprotective/neurorestorative treatment for
PD for promoting functional regeneration of the nigrostriatal sys-
tem. It has been shown in 6-OHDA-lesioned marmoset that the
delivery of low levels of GDNF expression, using AAV2 vector,
provides neuroprotection and induces behavioral recovery [ 38 ].
This benefi cial effect of viral GDNF expression or its analog neur-
turin on nigrostriatal degeneration and motor defi cits was con-
fi rmed in MPTP-treated rhesus monkeys [ 39 , 40 ]. Based on these
encouraging results, the bilateral intraputaminal injection of the
AAV2-neurturin (CERE-120) vector was evaluated for safety and