Developing BBB-permeable ASO to target ataxin-2 and mitigate TDP-43 proteinopathies for amyotrophic lateral sclerosis therapy

The cytoplasmic accumulation of TDP-43 in motor neurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS).

TDP-43 pathology is a component of 97% of amyotrophic lateral sclerosis (ALS) cases and nearly 50% of frontotemporal dementia cases (1). The molecular mechanism by which TDP-43 aggregation causes motor neuron degeneration is not fully understood. Currently, there are no effective TDP-43 therapies. Due to the myriad vital cellular roles of TDP-43, therefore, silencing or removal of TDP-43 is not desirable. Therefore, therapeutic strategies are being developed by targeting modifiers genes such as ataxin-2. It has been shown that reduction in ataxin-2 level suppresses TDP-43 toxicity in yeast and flies (2). In addition, the CNS reduction of ataxin-2 using antisense oligonucleotides has significantly increased the survival and motor function of TDP-43 mice (3).

Therefore, reducing the ataxin-2 level using ASO is an attractive therapeutic approach that is applicable to a broader population of patients with TDP-43 proteinopathy.


  • Identify ASOs for efficient knockdown of ataxin-2. Two classes of ASOs with different backbone chemistries and modes of action will be screened. (a) LNA targeting ataxin-2 RNA degradation through RNAase H mechanism and (b) PNA/PMO – translational blocking of ataxin-2.
  • Conjugate the most potent ASO chemistry to BBB-crossing peptides and in vitro effect on TDP-43 level, TDP-43 inclusion, etc.
  • Investigate the in vivo effect of P-ASO on the survival and motor function in TDP-43 mice.

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