Lentiviral Vectors in Huntington’s Disease Research and Therapy - Viral Vector Approaches in Neurobiology and Brain Diseases - page 187

the striatum [ 33 ]. This model is characterized by the rapid devel-
opment of striatal disease reproducing the typical characteristics of
HD, including the formation of Htt inclusions, neuronal dysfunc-
tion, astrogliosis and the neurodegeneration of GABAergic neu-
rons at 3 months. The mutant Htt gene was strongly overexpressed
(by a factor of up to 25; [ 34 ]), leading to the rapid appearance of
typical HD functional abnormalities closely mimicking the clinical
expression profi le observed in HD patients [ 35 ]. The injection of
mHtt-encoding LVs into rodents is currently used to dissect the
mechanisms underlying neuronal degeneration.
New models of neurodegenerative diseases have recently been
developed for investigating the contribution of astrocytes to the
disease [ 36 ]. Colin and coworkers used an LV specifi cally targeting
the astrocytes. This LV was pseudotyped with the G glycoprotein
of a lyssavirus, the MOK-G envelope, and contained an miR124T
detargeting sequence to inhibit transgene expression in neurons
[ 15 , 37 ]. Astrocytes expressing the mHtt gene progressively
develop a reactive phenotype, with decreases in glutamate trans-
porter expression and glutamate uptake, as observed in patients
with HD. This model suggests that astrocyte activation may con-
tribute to striatal dysfunction in HD. It constitutes a new approach
to understanding the disease and developing therapeutic approaches.
Another major advantage of LVs is the possibility they offer of
establishing models in different species, including large animals
such as nonhuman primates (NHPs), which closely resemble
humans in terms of neuroanatomy, motor behavior, and cognitive
characteristics. We have developed a Macaca fascicularis model of
HD involving the injection of mHtt into multiple sites in the puta-
men [ 38 ]. LVs expressing mHtt delivered to the putamen have
been shown to reproduce the motor defi cits observed in HD
patients. Following bilateral injections, animals display spontane-
ous chorea from 16 to 30 weeks and typical defi cits, such as head
dyskinesia and leg dystonia. Thus, LVs provide a fl exible, highly
effi cient and reliable system for localized and controlled produc-
tion of mutant Htt in the CNS, at low cost and over very short
periods of time. These rodent and primate HD models will greatly
facilitate the evaluation of therapeutic strategies.

The second application of LV gene transfer is gene therapy. Many
studies have shown that LVs can be used for the effi cient local and
continuous delivery of a therapeutic gene (secreted or intracellular
molecule) in the CNS. LV approaches lead to long-term, robust
transgene expression in the brain [ 18 , 19 ]. In the context of HD,
various disease-modifying treatments have been investigated,
including neuroprotective strategies based on ciliary neurotrophic
factor (CNTF) [ 39 - 41 ], chaperones [ 42 ], or the c-jun-N terminal
kinase pathway [ 43 ]. However, reducing the level of mHtt mRNA
itself would be the ultimate, most direct strategy for blocking

1.4.2 Lentiviral Vector
Gene Therapy