Gene Therapy for Huntington’s Disease - Gene Delivery and Therapy for Neurological Disorders - page 123

1.1 Neurotrophic
Factors

Neurotrophic factors are endogenously expressed growth factors
that promote neuronal growth and differentiation during develop-
ment but also have a continuous supportive role in the adult brain
[ 10 ]. The modulatory effects of neurotrophic factors on cell sur-
vival provide the rationale of developing therapies based on the
delivery of exogenous neurotrophic factors to the diseased brain
which may lead to neuroprotection or neuroregeneration. Several
neurotrophic factors delivered through gene therapy have shown
promise in animal models of HD. However, one should be aware
that these symptomatic treatment strategies only prevent neuronal
loss indirectly and do not target the pathogenesis of HD.

Nerve growth factor (NGF) is the first discovered and best charac-
terized member of the neurotrophin family [ 11 ]. NGF delivery by
transplantation of ex vivo modified cells into the lateral ventricles
[ 12 ] or striatum [ 13 ] of rats strongly protected GABA-ergic and
cholinergic neurons against intrastriatal injection of QA. In one
study, lesion size was reduced by as much as 60 % in animals which
received NGF-secreting neural stem cell (NSC) grafts compared to
controls [ 14 ]. In contrast, intrastriatal transplantation of mesen-
chymal stem cells (MSCs) genetically modified to overexpress NGF
into YAC128 transgenic mice expressing full-length human mHtt
protein led to modest improvements in motor function when the
rotarod and clasping tasks were performed but did not prevent the
loss of striatal DARPP-32-positive MSNs [ 15 ]. This is consistent
with a selective rescue of cholinergic interneurons but not MSNs
after i.v. administration of NGF [ 16 ]. These results suggest that
therapeutic response may be dependent on the route of adminis-
tration and differ between HD models.

1.1.1 Nerve
Growth Factor

Brain-derived neurotrophic factor (BDNF) has been extensively
studied as a therapeutic agent for HD due to its role in mediating
the differentiation and long-term survival of striatal MSNs [ 17 , 18 ].
Striatal BDNF is primarily produced in the cerebral cortex and
supplied to the striatum through anterograde transport along cor-
ticostriatal afferents [ 19 ]. Under normal conditions, wild-type Htt
binds to repressor element-1 transcription factor/neuron-restrictive
silencer factor to prevent its entry into the nucleus, thereby enhanc-
ing BDNF expression in cortical neurons. However, the polygluta-
mine expansion in mHtt reduces its binding efficiency, decreasing
BDNF transcriptional activity and protein levels in HD [ 20 ]. Low
striatal BDNF levels in HD may also be attributed to impairments
in a BDNF transport mechanism involving wild-type Htt [ 21 ].
Reduced levels of BDNF have been reported in the cerebral cor-
tex and striatum of HD patients [ 22 ] and in cell and mouse models
of HD [ 23 ], which may potentiate the onset and severity of motor
and cognitive deficits [ 24 , 25 ]. Moreover, lower serum BDNF lev-
els have been observed in HD patients with longer polyglutamine

1.1.2 Brain-Derived
Neurotrophic Factor