Essay Example on Potential novel therapy for ALS

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Potential novel therapy for ALS An antisense oligonucleotide 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 BETHAN CRITCHLEY 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

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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 TDP 43 aggregate formation Firstly Becker s group show that depletion of ataxin 2 significantly improves the lifespan of transgenic mice expressing human TDP 43 by slowing ALS progression and therefore improving muscle function They further demonstrate 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 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 hypothesise 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 provides novel insight into the mechanism of ataxin 2 s role in TDP 43 aggregation Their results support their hypothesis that the reduction of ataxin 2 in human cells in vitro inhibits TDP 43 aggregation as observed in the mouse model providing evidence that ataxin 2 reduction could be a viable human ALS therapy Finally Becker and colleagues test a potential therapy by injecting an ataxin 2 ASO into cerebrospinal fluid of the TDP 43 transgenic mice Figure 1B observing no adverse side effects and significantly improving lifespan and motor performance compared to controls These results provide hope for a broadly effective ASO ALS therapy in the near future Whilst these preliminary results hold significant promise and share many parallels with ASO therapies being trialled against other diseases including spinal muscular atrophy5 in humans 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 pre clinical 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 detection of disease is often difficult meaning that it is unlikely for treatment administration to begin prior to disease onset In order for scientists to assay 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 interacting 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 anticipated 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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