Application of Viral Vectors to Motor Neuron Disorders - Viral Vector Approaches in Neurobiology and Brain Diseases - page 213

1.1.1 Amyotrophic
Lateral Sclerosis

The molecular mechanisms underlying familial forms of ALS
(fALS) remain poorly understood. This is despite intense investiga-
tions made for more than a decade on pathogenic mutations in
several proteins including Cu/Zn SOD1, FUS, and TDP-43.
Remarkably, cellular and animal model systems based on the over-
expression of SOD1 carrying fALS mutations recapitulate many of
the cardinal features of the disease (for review on ALS animal mod-
els, see [ 3 ]), including the selective degeneration of vulnerable
pools of motor neurons [ 4 ]. Animal models follow a highly pre-
dictable disease course, in which mutated SOD1 induce complex
and redundant perturbations in various cellular processes that lead
to neuronal demise [ 5 ]. Although the clinical picture is mainly
determined by motor neuron loss, ALS is considered to be a non-
cell autonomous condition as astrocytes and microglial cells
expressing the pathogenic protein infl uence disease progression in
SOD1 animal models [ 5 - 10 ].
Viral vectors are gaining attention in the arsenal of experimental
tools used to explore in vivo this complex array of pathologic inter-
actions. The possibility to selectively transduce subsets of cells at
various stages of the disease represents a major advantage to deci-
pher how pathogenic determinants lead to motor neuron degenera-
tion. In addition, gene therapy represents a promising strategy to
possibly curb the progression of this fatal disease [ 11 ]. Viral vectors
are considered as a potential means to provide genetic information
that may support the survival of motor neurons [ 12 ]. Until now,
most approaches were based on the delivery of either trophic [ 13 -
16 ] or anti-apoptotic factors to motor neurons [ 17 ]. Alternatively,
the use of silencing instructions to directly target the expression of
pathogenic proteins, such as mutated SOD1, has been investigated
[ 18 , 19 ]. However, this strategy may work only in a subset of patients
where the targeted protein is an identifi ed cause of the disease.

SMA is the most frequent inherited cause of infant death. It is associ-
ated with mutations in the survival of motor neuron gene ( SMN1 )
that lead to a loss of expression and/or function of the SMN protein
[ 20 ]. Disease severity is modulated by the level of expression of the
SMN2 gene, a second copy of the SMN gene present in humans.
SMN2 mainly produces an alternatively spliced form of the SMN
protein, which lacks exon 7 and is therefore unstable. Hence, the
SMN2 gene only partially replaces SMN1 function. It is unclear how
the lack of functional SMN protein leads to motor neuron degenera-
tion. SMA is however as a monogenic disease a prime target for gene
therapy [ 21 ]. Viral vectors have been used to deliver the SMN gene
in severe mouse models of SMA, such as the SMN Delta 7 mice
[ 22 ]. The remarkable extension of survival observed following injec-
tion of viral vectors encoding SMN in diseased mouse neonates
highlights the therapeutic potential of gene therapy in the frame of
MNDs with an identifi ed genetic target [ 23 - 26 ].

1.1.2 Spinal Muscular
Atrophy