Stathmin-2 as a therapeutic target for Amyotrophic Lateral Sclerosis

Topic:

Gene targeted therapies

Poster Number: 217

Author(s):

Jone Lopez Erauskin, PhD, Ze'ev Melamed, PhD, Michael W. Baughn, Melinda S. Beccari, Frank Rigo, PhD, C. Frank Bennett, PhD, John Ravits, MD, PhD, Clotilde Lagier-Tourenne, MD, PhD, Don W. Cleveland, PhD

Institutions:

1. Ludwig Instituite for Cancer Research, 2. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA., 3. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA, 4. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA., 5. Ionis Pharmaceuticals, Carlsbad, CA, USA, 6. Ionis Pharmaceuticals, Carlsbad, CA, USA, 7. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA, 8. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 9. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.

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.