Gene Therapy for Huntington’s Disease - Gene Delivery and Therapy for Neurological Disorders - page 125

Direct transduction of striatal neurons with viral vectors may
overcome the problem of insufficient CNTF delivery. Unilateral
adenoviral gene transfer of CNTF into the striatum of rats dimin-
ished motor deficits and reduced lesion volume by 64 % following
systemic 3-NP infusion by comparison to the contralateral hemi-
sphere [ 37 ]. The treatment remained effective when administered
up to 3 months before lesioning. In contrast, lentiviral vectors
allowed stable, long-term CNTF expression in the striatum for up
to 1 year but reduced the number of NeuN- and DARPP-32-
positive cells in both wild-type and YAC72 transgenic mice [ 38 ]. It
is unclear why this occurs or how such an alteration may impact
neuronal functions. Furthermore, GFAP expression was upregu-
lated in the entire striatum of rats injected with lenti-CNTF, sug-
gesting a possible inflammatory response to widespread CNTF
diffusion. Adverse effects in the form of weight loss, motor, and
behavior abnormalities were also reported following striatal CNTF
overexpression mediated by AAV vectors in both transgenic HD
and wild-type mice [ 39 ]. These results illustrate a need to address
the side effects of long-term CNTF expression in future studies
before it can be pursued as a therapy.

Glial cell line-derived neurotrophic factor (GDNF) is the most
well-characterized member of the GDNF family of ligands. It is
produced in the striatum during development and expressed by
striatal projection neurons in adulthood [ 40 , 41 ]. GDNF binds to
GDNF receptor (GFR) complexes which signal through receptor
tyrosine kinase c-Ret to activate various cell survival pathways
including the Erk/MAP kinase pathway [ 42 ]. GDNF-secreting
NSC grafts transplanted in the striatum greatly reduced the extent
of neuronal loss and reversed amphetamine-induced rotational
behavior in nude mice with unilateral QA striatal lesion [ 43 ].
Similarly, striatal transplants of mouse neural progenitor cells
(mNPCs) transduced by lentiviral vectors to overexpress GDNF in
presymptomatic N171-82Q transgenic mice enhanced neuronal
survival up to 3 months posttransplantation and improved rotarod
test latency [ 44 ]. On the other hand, in vivo approaches of upreg-
ulating GDNF have yielded mixed results. AAV-mediated delivery
of GDNF into the striatum before insult significantly reduced the
extent of neuronal cell loss from QA lesioning [ 27 ] or systemic
3-NP injection in rats [ 45 ]. Bilateral injections of AAV-GDNF in
N171-82Q mice prior to the manifestation of behavioral symp-
toms improved performance in the rotarod and hindlimb clasping
tests, suggesting a delay in the onset of motor impairments. On the
anatomical level, GDNF overexpression reduced the density of
mHtt-positive inclusions and prevented striatal neuronal loss and
atrophy [ 46 ]. In contrast, no structural or functional neuroprotec-
tion was provided by lentiviral-mediated GDNF gene transfer in
4-5-week-old R6/2 transgenic mice, an HD model of chronic
neurodegeneration [ 47 ]. The mice showed no improvement in the

1.1.4 Glial Cell
Line-Derived
Neurotrophic Factor