Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery

Abstract

[Purpose] A key pathological hallmark of amyotrophic lateral sclerosis (ALS) is transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy. Mutations in TARDBP and cellular stress can drive nuclear clearance and cytoplasmic aggregation of TDP-43. TDP-43 is an essential nuclear RNA-binding protein that regulates RNA metabolism, and cytoplasmic TDP-43 aggregation leads to aberrant splicing of essential neuronal transcripts including stathmin-2 (STMN2) and unc-13 homolog A (UNC13A). Dysregulated RNA splicing causes cryptic exon (CE) inclusion in STMN2 and UNC13A mRNA, resulting in non-functional proteins and disruption of axonal regeneration and synaptic integrity. Splice-switching antisense oligonucleotides and gene-editing platforms can correct STMN2 and UNC13A mis-splicing defects. However, restoring STMN2 and UNC13A expression alone is not sufficient to regenerate neuromuscular junctions or reverse skeletal muscle atrophy, both of which are crucial for functional recovery in patients with ALS.[Methods] We reviewed gene-targeted treatment strategies and rehabilitative mechanisms that inhibit ALS progression and reverse neuromuscular degeneration by analyzing databases, including Google Scholar, PubMed, and ScienceDirect. We proposed a dual-modality therapeutic approach integrating base-editing-mediated gene therapy with exercise-based rehabilitation.[Results] Antisense oligonucleotides and genome editing can restore transcript fidelity by preventing cryptic exons inclusion in STMN2 and UNC13A, thereby stabilizing neuronal function. Gene-targeted therapies halt ALS progression; however, these treatments alone are insufficient to reverse neuromuscular degeneration or achieve functional recovery needed for patients with ALS to return to daily life.[Conclusion] Integrated rehabilitation is a crucial step in gene-targeted therapy for ALS. This strategy halts disease progression and restores neuromuscular function, thereby improving the lifespan and quality of life of patients with ALS.