CNCR joins TARGET ALS consortium to restore Stathmin2 expression

02 January 2023

Irune Guerra San Juan and Matthijs Verhage (FGA) became partners in an international consortium that designs and tests oligonucleotides to suppress poison exon insertion and restore full length Stathmin 2 expression in sporadic ALS

Following the recent successes on the identification of aberrant cryptic exon insertion in STMN2 transcripts due to TDP43 pathology, and the establishment of humanized STMN2 mouse models, the consortium will now attempt to suppress motor neuropathies in these mouse models and in patients using splice switching oligonucleotides.

More than 90% of patients with amyotrophic lateral sclerosis (ALS) exhibit insoluble cytoplasmic deposits of the RNA-binding protein TDP43. TDP43 is an important regulator of RNA metabolism and has been shown to influence many aspects of an RNA’s life cycle, ranging from its initial transcription to its splicing, transport, and translation. Recently, we and others have shown that the transcript encoding the protein STMN2/SCG10 is one of the most abundant in human induced pluripotent stem cell-derived motor neurons, that the STMN2 transcript is tightly regulated by TDP43 and that reduced TDP43 function caused premature polyadenylation of the STMN2 pre-mRNA, producing a truncated STMN2 message due to the retention of a cryptic (“poison”) exon. The consortium has designed oligonucleotides to suppress this poison exon insertion and restore full length Stathmin 2 expression despite reduced TDP43 function. We now aim to test how efficient these oligo’s suppress motor neuropathies in humanized Stmn2 mutant mice carrying a bacterial artificial chromosome containing the human STMN2 locus (the native murine gene does not contain the poison exon), in which TDP-pathology is induced. We have previously shown that mice deficient in Stmn2 exhibit motor neuropathy as demonstrated by loss of neuromuscular junction (NMJ) innervation, accompanied by evidence for a regenerative response to muscle injury, which was further associated with a significant deficit in motor behavior. Moreover, loss of Stmn2 was shown to result in alterations to microtubule polymerization in the neuronal fraction of the mouse lumbar spinal cord and in hPSC-derived motor neurons.
In parallel, these oligo’s are tested in clinical studies on ALS patients in N=1 trials and biomarkers for Stmn2 pathology (and reversal) are being developed.