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An antisense oligo nucleotide, which inhibits formation of toxic protein aggregates
in the central nervous system of an ALS mouse model, provides hope for a new
widely-applicable therapy for the disease.


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Amyotrophic lateral sclerosis
(ALS) is a fatal adult-onset neuromuscular disorder characterised by progressive loss of bulbar and/or spinal motor
neurons which leads to muscle
weakness, twitching and cramping. The cause is not well understood, yet 97%
of ALS patients have aggregates of TDP-43 present in their central nervous
system (CNS), making the protein an ideal target for ALS therapies. TDP-43 is
an RNA-binding protein which is involved in the process of gene expression and
regulation, therefore direct silencing of TDP-43 is unlikely to be an
appropriate option (as evidenced by the current lack of TDP-43-directed ALS therapies).
Becker et al.1 investigate a novel therapeutic strategy which indirectly
reduces levels of TDP-43 by lowering levels of ataxin-2 using an antisense
oligonucleotide (ASO).  

Mutations in the ataxin-2 gene
are not directly linked to ALS, however an earlier study by the same group2
identified that the gene is associated with ALS susceptibility, indicating that
the interaction between ataxin-2 and TDP-43 may be a candidate for therapeutic
intervention. In the present study, Becker et al. aim to investigate the
effects of ataxin-2 reduction in mice (initially by either partial or complete deletion,
followed by the more therapeutically-relevant strategy of ASO injection) and
explore the potential mechanism by which ataxin-2 regulates formation of TDP-43

Firstly, Becker’s group demonstrated that depletion of ataxin-2 significantly
improved the lifespan of transgenic mice expressing human TDP-43 by slowing ALS
progression and therefore improving muscle function. They further demonstrated
that ataxin-2 reduction did not affect the levels of TDP-43 in the CNS of these
mice, an important aspect considering the vital functions of TDP-433.
This supported their earlier work which suggested that ataxin-2 may be a viable
therapeutic target for ALS, however these findings did not provide any insight
into the mechanism by which ataxin-2 deletion acts upon TDP-43 aggregates.

Figure 1 | TDP-43 pathology in ALS and therapeutic ASO intervention (A) In ALS -affected
neurons, TDP-43 co-localises with cytoplasmic protein-RNA complexes known as
stress granules, which are toxic to the neuron (B) Ataxin 2 mRNA promotes the
assembly of stress granules, initiating the aggregation of TDP-43. These
aggregates are a common feature of ALS pathology. Becker’s paper proposes an
ataxin-2 ASO which extends the lifespan and reduces rate of muscular
degeneration in transgenic mice carrying human TDP-43 prone to aggregation.

Building upon previous theories that
TDP-43 aggregation in stress granules can lead to formation of toxic TDP-43
aggregated in ALS4, the group hypothesised that reducing ataxin-2 may
decrease TDP-43’s tendency to be recruited to stress granules and therefore
reduce TDP-43 aggregate formation (Figure 1). The supporting data produced by
the team provided novel insight into the mechanism of ataxin-2’s role in TDP-43
aggregation. They confirmed that the reduction of ataxin-2 in human cells in vitro inhibited TDP-43 aggregation (as
had been observed in the mouse model), providing evidence that ataxin-2
reduction could be a viable human ALS therapy.

Finally, Becker and colleagues tested
a potential therapeutic treatment by injecting an ataxin-2 ASO into
cerebrospinal fluid of the TDP-43 transgenic mice (Figure 1B), observing no
adverse side effects and significantly improved lifespan and motor performance
compared to controls. These results suggest that a broadly-effective ASO ALS
therapy may be viable in the near future.

Whilst these preliminary results
hold significant promise and share many parallels with ASO therapies being
trialled in humans (including an ASO effective against spinal muscular atrophy5),
there are still several unresolved issues and multiple further studies
required. Becker’s model elegantly provides evidence for the efficacy of
ataxin-2 ASO in reducing TDP-43 aggregation, however this is achieved by direct
manipulation of TDP-43 which embodies only a small subset of mutations
responsible for a limited number of ALS cases. Trials in animal models which
possess the mutations indirectly responsible for TDP-43 aggregation and ALS in
human patients represent a necessary and logical next step to determine if the
therapy is clinically viable. Future hopes rest upon longer-term preclinical trials
to assess the tolerance and long-term efficacy of the ataxin-2 ASO, and
subsequent human clinical trials if these prove successful.

As is the case in the wider field
of neurodegenerative disease therapy, questions surrounding the efficacy of the
ataxin-2 ASO once disease symptom onset has occurred will need to be addressed.
The design of clinical and pre-clinical trials to evaluate whether the ataxin-2
ASO is effective once ALS symptoms have manifested will be an important aspect
of the assessment of the treatment’s potential, as it is often unlikely when
treating neurodegenerative diseases that treatment administration begins prior
to disease onset.

In order for scientists to measure
the ASO’s action, it will be crucial to develop ataxin-2 and/or TDP-43 markers which
can be used in the CNS to determine whether the ASO is acting as expected. This
will not only provide confirmation of the action of the ataxin-2 ASO but could
also provide useful insight if trial results are not as expected (as has been
the case when several promising neurodegenerative disease therapies have been
tested in later-stage trials).

Despite these substantial challenges,
Becker et al.’s paper represents a landmark achievement in ALS treatment
research, and provide significant hope for a broadly-effective ASO therapy in clinical
trials and beyond.

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