Biology Reference
In-Depth Information
PD
Parkinson's disease
SN
Substantia nigra
STN
Subthalamic nucleus
TH
Tyrosine hydroxylase
1
Introduction
With the recent development of effective gene delivery systems,
gene therapy is fi nding novel applications for the treatment of neu-
rodegenerative disease such as Parkinson's disease (PD) [ 1 ] or
Alzheimer's disease (AD) [ 2 ]. The effectiveness of gene therapy is
closely dependent on the delivery strategies, the choice of vector
transgenes, the regulatory elements, and the capacity to transduce
the appropriate target cell type. Many of these approaches have
proven very hopeful in preclinical studies in rodents and nonhu-
man primates [ 3 , 4 ], and a substantial number are now being eval-
uated in clinical trials [ 5 - 7 ]. Recombinant viral vector systems
remain the most effi cient vehicles to achieve long-term stable gene
expression in the CNS. Among the different viral vector systems
used for CNS gene transfer studies, lentiviral vectors (LV) and
adeno-associated viruses (AAV) have emerged as promising vector
due to their simplicity, their excellent safety profi le, and their rela-
tively ease of production. In this chapter, we discuss recent devel-
opments in the delivery of viral vectors, particularly in nonhuman
primate with special focus on PD.
2
Lentiviral Vectors
LVs have the ability to effi ciently transduce nondividing and divid-
ing cells, to insert large genetic segment in the host chromatin, and
to sustain stable long-term transgene expression (for review see [ 8 ]).
The effi ciency of lentiviral transduction was tested in rhesus mon-
keys using a vector encoding for the marker
-galactosidase injected
in striatum or in substantia nigra. A robust transduction of striatal
and nigrals cells was observed as 90 % of neurons were transfected
up to 3 months [ 9 ] and no evidence of an immune response or
infl ammation was observed. These promising data highlight the
potential clinical application of this system for neurologic disorders
characterized by anatomically circumscribed pathophysiology such
as PD. One therapeutic approach using LV consists of overexpress-
ing trophic factors that provide support for the dying dopaminergic
nigral cells from the SN. Numerous gene delivery data in rodent and
primate models of PD has placed glial cell line-derived neurotrophic
factor (GDNF) to the vanguard of PD neuroprotective therapy [ 10 ]
based on its capacity to restore function and prevent degeneration of
dopaminergic neurons against [ 11 ]. Intracerebral injection of
β
 
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