Application of Viral Vectors to Motor Neuron Disorders - Viral Vector Approaches in Neurobiology and Brain Diseases - page 215

1.3 Route of Delivery

Viral vectors can effi ciently transduce various types of post-mitotic
cells in the CNS, including motor neurons both in the motor cortex
and spinal cord. However, despite the relatively low total number of
motor neurons innervating skeletal musculature, their cell bodies are
distributed throughout the motor cortex, brainstem, and spinal cord.
Therefore, transducing enough motor neurons in mammalian organ-
isms to support vital motor functions is a major challenge. Direct
injections either in the spinal cord or in the motor cortex locally
transduce neurons, but they necessitate invasive surgical procedures
that cannot be applied to the entire motor pathway. To circumvent
this limitation, various routes of vector delivery have been explored.
Injection to the bloodstream is an attractive alternative to
broadly distribute viral vectors inside the organism. However, as
vector particles do not usually cross the BBB, this approach is gen-
erally considered poorly effective for the CNS. Surprisingly, certain
AAV serotypes display a specifi c ability to cross the BBB. Notably,
intravenous injections of serotype 9 AAV vectors in adult mice and
cynomolgus macaques lead to consistent astrocyte transduction
throughout the CNS [ 29 , 34 ]. Interestingly, the same AAV sero-
type injected intravenously can also transduce neuronal cells both
in neonate [ 29 , 31 ] and adult mice [ 30 ]. Although the mecha-
nisms involved remain unclear, these results indicate that the deliv-
ery of viral vectors to the CNS via the blood vasculature should be
thoroughly investigated.
Some viruses display a natural ability to transduce neurons from
their axons and nerve terminals via retrograde transport of viral par-
ticles to neuronal cell bodies. Advantage has been taken of this retro-
grade transport property to design viral vectors that can effi ciently
infect neurons following intramuscular or intraneural [ 35 ] injections.
These vectors are often based on viruses such as rabies and herpes
viruses that are known to retrogradely infect neurons in humans.
However, human (hAdV) and canine (CAV-2) adenoviruses [ 36 ,
37 ], as well as AAV vectors [ 32 , 33 , 38 ], can also effi ciently retro-
gradely transduce neurons following intramuscular injection. The
presence of the myelin sheath might however reduce transduction of
axons using viral vectors in adults. Transient demyelination induced
by injection of ethidium bromide in the muscle was reported to
enhance the retrograde transduction of motor neurons using AAV
vectors [ 39 ]. Targeting motor neurons following intramuscular
injection of recombinant particles can provide local therapeutic
effects at the level of the injected muscle [ 33 ]. It is however unclear
if the same approach would be applicable to diseases characterized by
neurodegeneration across the entire spinal cord [ 40 , 41 ].
Alternatively, widespread transgene delivery in the CNS can be
achieved by injecting viral vectors in the cerebrospinal fl uid (CSF)
[ 42 ]. This approach is particularly effective in the neonate CNS,
where axonal fi bers are not myelinated yet. Intracerebroventricular
(ICV) injection of AAV vectors leads to high levels of transduction