A landmark contribution to understanding amyotrophic lateral sclerosis (ALS) came from the discovery of cytoplasmic accumulation of the RNA/DNA binding protein TDP-43 in affected neurons of almost all instances of ALS. Besides TDP-43 cytoplasmic accumulations, nuclear clearance of TDP-43 has been extensively observed in affected neurons in sporadic ALS, evidence strongly supporting the proposal that TDP-43 loss of function is a key aspect of disease mechanism underlying ALS pathogenesis.
We have recently identified that the mRNA encoding stathmin-2 is the most affected mRNA upon reduction of TDP-43 function. Loss of TDP-43 enables premature polyadenylation of stathmin-2 producing a non-functional truncated form of stathmin-2 mRNA. Stathmin-2 is strikingly lost from motor neurons in sporadic ALS and in the most common form of inherited disease of GGGCCC expansion in C9orf72. Furthermore, we have demonstrated that stathmin-2 is essential for axonal regeneration of axotomized iPSC-derived motor neurons. Thus, we propose that recovering stathmin-2 levels is an attractive therapeutic strategy for sporadic and familial ALS patients.
We have now identified RNAase-H resistant antisense oligonucleotides (ASOs) that block the use of stathmin-2’s premature polyadenylation sequence and enable the rescue of stathmin-2 mRNA and protein levels upon TDP-43 depletion. The non-functional truncated form of stathmin-2 mRNA produced upon TDP-43 loss is also reduced in a dose-dependent manner after stathmin-2 rescuing ASO treatment. Most strikingly, stathmin-2 rescuing ASOs also restore axonal regeneration capability in human iPSC-derived motor neurons with reduced levels of TDP-43.
These data suggest that identified stathmin-2 rescuing ASOs have high therapeutic relevance for ALS and open the possibility for a clinically feasible therapeutic approach that may benefit the vast majority of ALS patients including sporadic and familial ALS cases.