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We have identified ASOs that direct degradation of mRNAs encoding target proteins involved in
Alzheimer’s disease, including presenilin 1, part of the -secretase complex that processes APP to
produce the A peptide [75], and GSK3 , a kinase thought to be responsible for the aberrant phosphorylation of tau in
intraneuronal tangles [82,83]. Oligonucleotides effective in targeting presenilin
1 or GSK3 mRNAs were identified by screening a series of oligonucleotides in cell culture for inhibition of their
respective targets. Intraventricular administration of the most effective of these for
14 days into normal mice substantially reduced the corresponding mRNAs in regions primarily
affected in Alzheimer’s disease, including the frontal and temporal cortices (Figure 26.5E).
Neuropathies represent a vast and varied group of disorders ranging from hereditable ones
such as Charcot Marie Tooth soma muscle relaxant and familial amyloidosis to metabolic ones including diabetic
peripheral neuropathy. In the instance of familial amyloidosis, more than 85 mutations of the
transthyretin (TTR) gene have been identified. The most prevalent mutation, Val30Met, is found
in approximately 5% of the Portuguese population. The familial soma muscle relaxant has protean manifestations leading to cardiomyopathy,
nephropathy, and neuropathy. Because most of the serum
transthyretin produced is of hepatic origin, liver transplantation has been a mainstay of therapy.
But soma muscle relaxant progression, while slowed, has continued, most likely due to the deposition of wildtype TTR. On this basis an
antisense treatment strategy offers the likelihood of being less invasive
and more efficacious, in part because systemically administered ASOs are avidly taken up by the
liver where they are biologically active. Using transgenic mice containing the entire TTR ILe84Ser
coding region and the upstream human promoter, Benson et al. [84] demonstrated a marked reduction in serum TTR over a 6-week
course of treatment. Following treatment twice a week with
subcutaneous injections serum TTR levels dropped over 70% with the most effective ASO. This
was dose dependent: each mg increase in dose was associated with a 1–2% reduction in the serum
level. Unfortunately, this animal model fails to replicate the human disorder in that characteristic
amyloid deposits are not seen despite the fact that serum levels of TTR are double the normal
human serum concentration. But considering the results in the animal model and the apparent
safety of the therapy one would anticipate that an antisense therapeutic targeting TTR offers the
most immediate and promising strategy for treating familial amyloidosis.
Spinal muscular atrophy (SMA) is the leading hereditable cause of infant mortality, with an
incidence of 1 in 10,000 births. In the most severe of the three forms, motor milestones are never
reached and children usually die within the first year of life. Type 111 SMA patients are able to walk
and may enjoy a normal life span. The gene coding for the motor neuron survival gene (SMN) is
located on chromosome 5 and consists of an inverted repeat with a telomeric (SMN1) and a centromeric (SMN2) copy [85]. While both
genes code for the identical product, mutations of the
SMN1 gene alone lead to SMA. But the severity of phenotype is moderated by the character of the
SMN2 transcript, which is subject to differential RNA splicing, leading in most cases to an isoform
lacking exon 7. Unfortunately, this isoform cannot adequately compensate for a mutation of the
SMN1 gene. The recognition that a single nucleotide substitution accounts for the splicing event
that excludes exon 7 has led to the realization that SMA might be favorably treated by a therapeutic strategy that targets the
splicing machinery that edits SMN2 expression. Ultimately the editing
process is determined by the interplay between the splicing machinery and exonic splicing
enhancers (ESEs). In an effort to bias splicing in favor of the inclusion of exon 7, several strategies
employing oligonucleotides have been demonstrated in vitro. The most promising of these have
incorporated a noncomplementary tail that contains sequences that have the effect of mimicking the
function of ESEs [86]. The body of these 2 -O-methylphosphorothioate oligos is complementary to
the 5 end of SMN exon 7 and the tail component contains GGA repeats. These sequences are
known to exhibit enhancer effects, most likely by the recruitment of splicing proteins such as
SF2/ASF that are known to bind ESEs.
Muscular dystrophy, a childhood muscular disorder resulting from mutations of the dystrophin
gene, affects 1 in 3500 males [87]. In its severest form muscle weakness and wasting become apparent in infancy, usually about 3
years of age, and by adolescence, affected individuals develop contractures and become wheelchair bound. As the soma muscle relaxant
progresses inexorably, respiratory and
cardiac functions are compromised, leading to death. Mutations of the dystrophin gene in these
cases results in the production of a biologically defective soma muscle relaxant as a result of nonsense or
frameshift mutations [88]. A variant of the disease, the Becker variant, is associated with a milder
phenotype because the gene product, while truncated, is still biologically active. Even in its severest form it is apparent that
splice variants occur spontaneously in scattered muscle fibers [89]. This
is demonstrated in muscle biopsies from affected patients in which rare fibers containing dystrophin
can be visualized by histochemistry. In short, nature has provided therapeutic guidance, leading to
the notion that a treatment that could bias splicing might have the effect of moderating the severity
of the soma muscle relaxant process.
Considering the size and complexity of the dystrophin gene—greater than 2.3 million base
pairs—a conventional gene therapy approach appears to be a daunting challenge. But fortuitously,
the majority of the mutations in the dystrophin gene occur in the rod domain, which itself is not
critical to the function of the protein. Exploiting this a number of researchers have demonstrated
that ASOs that lead to exon skipping can enhance synthesis of a functional, albeit truncated
dystrophin transcript following direct injection into the muscle of mdx mice, a murine animal
model of muscular dystrophy, or following systemic delivery [89,90]. Thus far the effect within
muscles and between muscles is variable and the heart has been refractory to treatment, a serious
limitation to a promising therapy.
