Lentiviral Vectors in Huntington’s Disease Research and Therapy - Viral Vector Approaches in Neurobiology and Brain Diseases - page 184

Chapter 11

Lentiviral Vectors in Huntington's Disease Research
and Therapy

Aurélie Delzor , Noëlle Dufour , and Nicole Déglon

Abstract

We describe here the potential of viral-mediated gene transfer for the modeling and treatment of
Huntington's disease, focusing in particular on strategies for the tissue-specifi c targeting of various CNS
cells. The protocols described here cover the design of lentiviral vectors, strategies for modifying their
tropism, including the use of various envelopes and tissue-specifi c promoters, and the potential of miRNA
to regulate transgene expression.

Key words Lentiviral vectors, Tissue-specifi c promoters, Pseudotyping, miRNA gene regulation,
CNS, Huntington's disease

1 Introduction

1.1 Huntington's
Disease

Huntington's disease (HD) is a disabling, fatal neurodegenerative
disorder that occurs in adulthood. Its principal symptoms are cog-
nitive defi cits and chorea, characterized by involuntary movements
of large amplitude [ 1 ]. Only symptomatic treatments, such as neu-
roleptics, antidepressants, and anxiolytics drugs, are currently
available [ 2 - 4 ]. HD is caused by an abnormal CAG expansion in
the huntingtin (Htt) gene, leading to a selective loss of neurons in
the striatum and, at more advanced stages, in other brain areas
[ 5 - 7 ]. The most severely affected brain area, the striatum, consists
of 95 % gamma-amino butyric acid (GABAergic) medium spiny
neurons (MSNs) and 5 % interneurons. Both these cell types pro-
duce the mutant Htt (mHtt), but the disease has been shown to
preferentially affect MSNs, with little effect on interneurons [ 8 , 9 ].
Moreover, striatopallidal neurons (indirect pathway) have been
shown to be more sensitive to neurodegeneration than striatoni-
gral neurons (direct pathway; [ 10 , 11 ]). There is also growing evi-
dence to suggest that mHtt interferes with the normal functions of