Application of Viral Vectors to Motor Neuron Disorders - Viral Vector Approaches in Neurobiology and Brain Diseases - page 212

Chapter 12

Application of Viral Vectors to Motor Neuron Disorders

Elisabeth Dirren and Bernard L. Schneider

Abstract

Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are
characterized by the progressive loss of motor neurons in the spinal cord and primary motor cortex.
Subsequent paralysis of skeletal muscles leads to variable degrees of motor impairment and is inevitably
fatal in ALS and type I SMA. A genetic cause has been defi ned for some of these conditions including
SMA. Therefore, motor neuron disorders could become prime targets for gene therapy provided effi cient
tools can be designed to specifi cally target widely distributed motor neurons. Here, the application of viral
vectors with a neuronal tropism is reviewed in the context of gene delivery to spinal lower motor neurons.
The preparation of adeno-associated vector suspensions for motor neuron infection is described. Finally,
we emphasize the use of intramuscular and intracerebroventricular delivery of adeno-associated vectors for
the specifi c targeting of motor neurons.

Key words Motor neuron, Amyotrophic lateral sclerosis, Spinal muscular atrophy, Gene therapy,
Adeno-associated vector, Retrograde transport, Neuroprotection

1 Introduction

1.1 Viral Vectors
for Basic Research
and Gene Therapy in
Motor Neuron
Disorders

Motor neuron disorders (MNDs) are a broad group of diseases
characterized by the selective and progressive loss and/or dysfunc-
tion of cortical and spinal motor neurons, which results in various
degrees of muscle weakness. MNDs notably include amyotrophic
lateral sclerosis (ALS), spinal muscular atrophy (SMA), and pri-
mary lateral sclerosis. There is currently no available treatment to
halt the progression of MNDs. Patients usually succumb of respira-
tory complications in ALS and severe forms of SMA. There is an
expanding list of genetic alterations, which were found to either
cause or increase the risk for MNDs (for recent reviews on ALS
and SMA, see [ 1 , 2 ]). Therefore, the development of gene delivery
systems to target motor neurons has been a fi eld of intense investi-
gation. In particular, viral vectors are being extensively used to (1)
explore how modifi cations of gene expression critically determine
neuronal vulnerability to disease-causing factors and (2) devise
effective strategies for gene therapy against MNDs.