Gene Therapy for Parkinson’s Disease - Viral Vector Approaches in Neurobiology and Brain Diseases - page 174

cyclohydrolase 1 (GCH1) into the striatum. Studies using this
strategy have reported an increase in DOPA or dopamine levels in
striatum and an improvement in motor behavior in rat models of
PD [ 1 , 2 ]. A reversal or prevention of dyskinesia, a common side
effect of oral L -DOPA treatment, has also been reported [ 2 , 3 ]. (2)
The prodrug approach aims to increase the striatal L -DOPA
conversion effi ciency by introducing the gene of the L -DOPA
converting enzyme L -amino acid decarboxylase (AADC) into the
striatum. Increased levels of striatal dopamine and behavioral effects
have been reported in studies using this strategy in rat and primate
models of PD [ 4 , 5 ]. Benefi cial effect on motor symptoms has also
been reported in two recent clinical trials [ 6 , 7 ]. (3) The dopamine
delivery approach aims to increase striatal dopamine levels by
introducing the genes of the dopamine synthesizing enzymes TH,
AADC, and GCH1 into the striatum. This strategy has been
evaluated in rat and primate models of PD, showing increased levels
of dopamine in striatum and benefi cial effects on motor behavior
[ 8 , 9 ]. Oxford BioMedica has developed a vector based on this
strategy, ProSavin, for clinical testing and is currently conducting a
Phase I/II trial on patients with PD [ 10 ]. No serious adverse events
correlating to the vector have been reported in any of these studies.
The loss of nigrostriatal dopamine seen in PD causes several
changes in the signaling throughout the basal ganglia circuitry.
One of the effected nuclei, the subthalamic nucleus (STN), shows
an overactivity in PD and lesion or deep brain stimulation (DBS)
of this nucleus has been shown to alleviate the motor symptoms
associated with PD [ 11 , 12 ]. These benefi cial effects on motor
symptoms lead to the development of a novel gene therapy para-
digm designed to decrease the effect of the overactive glutamater-
gic signaling from the STN on downstream targets. These gene
therapy studies use adeno-associated virus (AAV) expressing glu-
tamic acid decarboxylase (GAD), the rate-limiting enzyme in the
production of the inhibitory neurotransmitter GABA, to increase
the GABAergic output from the STN. Indeed, early studies using
the 6-OHDA rat model of PD have shown that AAV-GAD gene
therapy is able to increase the inhibitory output from the STN and
confer a benefi cial effect on motor behavior [ 13 , 14 ]. Benefi cial
effects on PD symptoms were later reported in a study using non-
human primates and in two clinical trials [ 15 - 17 ]. Increased
metabolism in the motor cortex [ 15 , 17 ] and decreased metabo-
lism in the thalamus [ 17 ] was also shown using PET imaging. No
serious adverse events have been reported in these studies, indicat-
ing that AAV-GAD gene therapy is safe.
As mentioned above, there is a loss of nigrostriatal dopamine in
PD. This loss of dopamine is due to the progressive loss of the
dopaminergic neurons in the substantia nigra pars compacta
(SNpc). Gene therapy using neurotrophic factors has the potential