366
J. Qu and J. Zhang
Therapeutic Strategies Targeting mHTT
One DNA aptamer, 20-mer G-rich oligonucleotides isolated by Skogen et al. in
2006, could adopt a G-quartet conformation to effectively inhibit mHTT aggregation,
although the mechanism is not clear. Besides, this aptamer could also enhance the
viability of PC12 cells which overexpressed the mHTT fragment gene [105].
In order to block mHTT aggregation, it is a good idea to bind to the mHTT
monomer. RNA aptamers, against monomeric mHTT, were selected by Chaudhary
et al., and they found these aptamers could not only inhibit its aggregation in vitro by
stabilizing the monomer, but also rescue the endocytotic defect, diminish oxidative
stress, and enhance cell survival due to aggregation of mHTT [103]. Subsequently,
they also evaluated the effect of these aptamers on mitochondrial dysfunction, which
is a hallmark of HD. They found these aptamers could reduce oxidative stress and
associated damage in a yeast model of HD. In addition, aptamers could also facilitate
the restoration of calcium homeostasis and improve cell viability [106]. Additionally,
a set of DNA aptamers, binding to the C-terminal CTD-II domain of mHTT, could
not only ameliorate metabolic deficits of HD phenotype, but also enhance the ability
to combat starvation-mediated stress in HD neuronal progenitor cells [104].
In brief, these aptamers against mHTT have been employed as tools to not only
discriminate between HTT and mHTT, but also inhibit the aggregation of mHTT
(Table 12.4), which hints aptamers could be used as reagents to diagnose and therapy
of HD (Fig. 12.3).
12.3 Conclusions and perspectives
Aptamers have gained great attention since their introduction in the early 1990s.
Aptamers are a class of substances having similar functions to classical antibodies,
but they have unambiguous advantages over classical antibodies, including small
size, low or no toxicity, and low immunogenicity. The obvious merits had driven
the aptamers to be widely used in the clinic such as cancer, eye, and inflammatory
diseases [107, 108]. Pegaptanib is the first and sole aptamer successfully applied
in the clinic, which is the milestone of aptamers to be used in the diseases. Many
other aptamers are being developed, which indicates more and more aptamers might
be applied to the neurodegenerative disorders [109]. Neurodegenerative disorders
are characterized by neuronal dysfunction and death, and most of these diseases
are associated with the accumulation of misfolded proteins in the central nervous
system. Aptamers against these targets which are associated with these diseases
have been developed, and some of them are being applied in clinical trials. Along
with the advancements of the technologies, such as nanotechnology, microfluidics,
microarray, and others in the field of clinical diseases, aptamer will gain its special
area in the clinic application.
This chapter demonstrated several aptamers used for neurodegenerative disorders,
but their number is very low compared with those that are applied in other pathologies
J. Qu and J. Zhang
Therapeutic Strategies Targeting mHTT
One DNA aptamer, 20-mer G-rich oligonucleotides isolated by Skogen et al. in
2006, could adopt a G-quartet conformation to effectively inhibit mHTT aggregation,
although the mechanism is not clear. Besides, this aptamer could also enhance the
viability of PC12 cells which overexpressed the mHTT fragment gene [105].
In order to block mHTT aggregation, it is a good idea to bind to the mHTT
monomer. RNA aptamers, against monomeric mHTT, were selected by Chaudhary
et al., and they found these aptamers could not only inhibit its aggregation in vitro by
stabilizing the monomer, but also rescue the endocytotic defect, diminish oxidative
stress, and enhance cell survival due to aggregation of mHTT [103]. Subsequently,
they also evaluated the effect of these aptamers on mitochondrial dysfunction, which
is a hallmark of HD. They found these aptamers could reduce oxidative stress and
associated damage in a yeast model of HD. In addition, aptamers could also facilitate
the restoration of calcium homeostasis and improve cell viability [106]. Additionally,
a set of DNA aptamers, binding to the C-terminal CTD-II domain of mHTT, could
not only ameliorate metabolic deficits of HD phenotype, but also enhance the ability
to combat starvation-mediated stress in HD neuronal progenitor cells [104].
In brief, these aptamers against mHTT have been employed as tools to not only
discriminate between HTT and mHTT, but also inhibit the aggregation of mHTT
(Table 12.4), which hints aptamers could be used as reagents to diagnose and therapy
of HD (Fig. 12.3).
12.3 Conclusions and perspectives
Aptamers have gained great attention since their introduction in the early 1990s.
Aptamers are a class of substances having similar functions to classical antibodies,
but they have unambiguous advantages over classical antibodies, including small
size, low or no toxicity, and low immunogenicity. The obvious merits had driven
the aptamers to be widely used in the clinic such as cancer, eye, and inflammatory
diseases [107, 108]. Pegaptanib is the first and sole aptamer successfully applied
in the clinic, which is the milestone of aptamers to be used in the diseases. Many
other aptamers are being developed, which indicates more and more aptamers might
be applied to the neurodegenerative disorders [109]. Neurodegenerative disorders
are characterized by neuronal dysfunction and death, and most of these diseases
are associated with the accumulation of misfolded proteins in the central nervous
system. Aptamers against these targets which are associated with these diseases
have been developed, and some of them are being applied in clinical trials. Along
with the advancements of the technologies, such as nanotechnology, microfluidics,
microarray, and others in the field of clinical diseases, aptamer will gain its special
area in the clinic application.
This chapter demonstrated several aptamers used for neurodegenerative disorders,
but their number is very low compared with those that are applied in other pathologies