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Targeting STMN2 Splicing to Treat ALS

Today’s post is a “SNiP” or Small News in Pieces. In each bite-size SNiP, we highlight an inspiring research article that features Mirus Bio products. This SNiP is a ray of hope in the search for a cure for amyotrophic lateral sclerosis (ALS).

A hallmark of almost all cases of ALS and many cases of frontotemporal lobar dementia is the loss of the RNA/DNA binding protein TDP-43 in the nucleus of neurons.1,2 TDP-43 regulates expression and pre-mRNA processing of several genes including STMN2, whose expression was recently shown to be highly enriched in motor neurons and critical for their growth and regeneration.3 Neurons from ALS patients have decreased expression of the full-length STMN2 gene product, stathmin-2, and an enrichment of a truncated form due to use of a cryptic exon (exon 2a), as shown in the figure below.

Diagram of the STMN2 gene and alternative splicing that leads to decreased stathmin-2 protein expression and motor neuron function.

Baughn & Melamed et al. show TDP-43 likely prevents cryptic splicing of STMN2 mRNA by simple binding and steric hindrance of exon 2a. Thus, they hypothesized that binding by antisense oligonucleotides or by a CRISPR/Cas enzyme at the cryptic exon could also prevent cryptic splicing of STMN2 in neurons lacking nuclear TDP-43, such as neurons that are affected by ALS. They identify antisense oligonucleotide and gRNA sequences that reduce exon 2a usage in vitro and in humanized mouse models. Check out the paper for details on how these gene therapies performed!

Note: As of April 2023, a Phase 1 randomized, blinded clinical trial is underway to evaluate the safety of an STMN2-directed antisense oligonucleotide in patients living with ALS.4



Title: Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies
Authors: Michael W. Baughn, Ze’ev Melamed et al.
Journal: Science, Volume 379, 17 March 2023.
DOI: 10.1126/science.abq5622
Product Usage: HEK 293T cells were transfected with TransIT-VirusGEN® to produce lentivirus for multiple studies in SH-SY5Y model cell lines. In one study, the lentivirus was used to deliver an inducible cassette for a STMN2 pre-mRNA binding protein. In another study, 11 dCasRx lentiviral vectors were constructed which harbored RfxCas13d and gRNA sequences targeting regions surrounding the exon 2a sequence in STMN2 pre-mRNA.


Find more publications using TransIT-VirusGEN® in the Mirus Citations Database.


  1. M. Neumann, et al.Science (2006).
    DOI: 10.1126/science.1134108
  2. J. Sreedharan, et al.Science (2008).
    DOI: 10.1126/science.1154584
  3. J. R. Klim, et al.Nature Neuroscience (2019).
    DOI: 10.1038/s41593-018-0300-4
  4. ClinicalTrials.gov, A Study Evaluating the Safety and Tolerability of QRL-201 in ALS. Identifier: NCT05633459.

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