Biomedical Engineering Reference
In-Depth Information
Currently, there is no cure for HD and treatment options for HD are primarily
focused on symptomatic relief with neuropsychiatric drugs (antipsychotics, anti-
depressants), speech therapy, and physical rehabilitation. Rodent and nonhuman
primate models of HD that are based on lesioning the striatum with excitotoxins
(i.e. ibotenic acid, quinolinic acid) showed encouraging cell transplantation results
and led to early phase clinical trials [
101
]. These open-label clinical trials were
performed over the last decade and indicated slowed disease progression when
grafting fetal striatal neuroblasts derived from ganglionic eminences at
7-10 weeks postconception [
102
]. Although beneficial effects were transient and
observed in only a few HD patients, this experience is a valuable foundation for
future cell replacement strategies [
102
-
104
]. At present, practical problems such
as finding a renewal source for donor cells of the correct phenotype, standardi-
zation of procedures, and criteria of patient selection are the main obstacles that
need to be overcome before personalized cell transplantation regimens for HD can
move toward the clinic.
1.7.4 Motor Neuron Diseases
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a devas-
tating neurodegenerative affliction affecting large motor neurons (MNs) localized in
the primary motor cortex (upper MNs) and ventral horns of the spinal cord (lower
MNs). The prognosis for ALS is poor and more than 90 % of the patients die within
2-5 years after diagnosis. The vast majority of the cases are sporadic and the
underlying cause is unknown. Of the familial cases (*10 %), missense mutations in
the Cu/Zn superoxide dismutase gene SOD1 have provided important insights into
the pathogenesis of ALS. Oxidative stress, mitochondrial dysfunction, and excito-
toxic damage are likely to be important mechanisms that ultimately lead to MN death
[
105
,
106
]. Importantly, it turned out that cell autonomous deficits of MNs are not the
only pathogenetic cause of ALS. In fact, astrocytes neighboring MNs critically
support their health and function but can also mediate noncell autonomous toxic
effects during disease and thereby contribute to MN loss [
106
-
109
]. Functional MNs
have been generated from mouse and human ES cells [
110
,
111
]. Neuronal cells
sharing molecular characteristics with bona fide MNs (e.g. expression of transcrip-
tion factor HB9, choline acetyltransferase) were generated also by exploiting iPS
cells and transcription factor-based induced neurogenesis [
112
,
113
]. Together, these
cells generated ex vivo are highly valuable for disease modeling and drug discover
but it is currently unclear if MN replacement per se might be a realistic clinical
approach. To restore functional motor circuits, de novo formation of long-distance
axonal projections would be necessary to innervate appropriate muscle fibers in the
periphery. Reconstruction of motor pathways is particularly challenging in the
molecular environment provided the adult mammalian CNS. Surface molecules
expressed by oligodendrocytes (e.g. Nogo proteins) inhibit axonal growth after
injury
[
114
].
Nevertheless,
transplantation
of
MNs
or
glial
cells
that
exert
