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.

References:

Ling, S.C., Polymenidou, M. & Cleveland, D.W., 2013. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron, 79, pp.416–438.

Elden, A.C. et al., 2010. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature, 466, pp.1069–1075.

Becker, L.A. et al., 2017. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature, 544, pp.367-371.