Viral Vectors in Primate Research: Examples from Parkinson’s Disease Research - Viral Vector Approaches in Neurobiology and Brain Diseases - page 321

LV-GDNF into MPTP-treated monkeys has resulted in persistent
protection of the nigrostriatal dopaminergic pathway and recovery
of motor function [ 12 , 13 ]. Further, in the same model, injection of
a tricistronic LV approach in encoding the critical genes for dopa-
mine synthesis, e.g., tyrosine hydroxylase (TH), aromatic L -amino
acid decarboxylase (AADC), and guanosine 5 -triphosphate cyclo-

hydrolase 1 (GCH) into the striatum safely restored extracellular
concentrations of dopamine and corrected the motor defi cits for 12
months without associated dyskinesias [ 14 ]. Using these vectors, a
phase I/II clinical trial in patients with PD was initiated.
In addition to the neuroprotective/neurorestorative
approaches, managing the symptoms by acting on the altered
dopamine neurotransmission in basal ganglia has been the most
investigated approach. The major current symptomatic manage-
ment strategy for PD utilizes a pharmacologic strategy to supply
the missing neurotransmitter, dopamine by using L -3,4-
dihydroxyphenylalanine ( L -DOPA), the precursor to dopamine for
alleviating PD symptoms [ 15 ]. However, long-term L -DOPA ther-
apy for PD becomes less effective and produces side effects
( L -DOPA-induced dyskinesia or LID) at doses required to treat
progressive PD [ 16 ]. One of the most PD preclinical gene therapy
efforts were focused at counteracting the development of LID
either by dampening their severity or by preventing their develop-
ment. Within the last decade, several targets such as the level of
dopaminergic receptors, transcription factors, and intracellular cas-
cades have been identifi ed in the development or expression of
LID. In this context, dopaminergic receptors have been shown to
be still overrepresented at the membrane surface while one would
have expected them to be internalized [ 17 ]. It therefore suggests
that they are still available for continuing stimulation and a puta-
tive gene therapy strategy could therefore be to promote the inter-
nalization process. Interestingly, in parkinsonian monkeys, loss of
dopamine leads to the upregulation of several G protein-coupled
receptor kinase (GRKs) [ 18 ], which may temper dopaminergic sig-
naling on initial L -DOPA administration and ensure a therapeutic
response to the drug. However, chronic L -DOPA treatment sup-
presses the GRK expression [ 18 ]. It has been proposed that
reduced GRK availability likely contributes to the exaggerated
dopaminergic signaling in the dyskinetic brain. Conversely, increas-
ing the capacity of the desensitization machinery in the parkinso-
nian striatum may ameliorate LID. Indeed, lentiviral-induced
striatal overexpression of G protein-coupled receptor kinase 6
(GRK6) led to an internalization of D1 receptors in the dyskinetic
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned
macaque [ 4 ]. GRK6 suppressed dyskinesia in monkeys without
compromising the antiparkinsonian effects of L -DOPA and even
prolonged the antiparkinsonian effect of a lower dose of L -DOPA
[ 4 ]. D2 also appear to be involved in dyskinesia. Although both

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