# RNA Interference and Its Key Targets for Spinal Cord Injury Therapy: What Is Known So Far?

## TL;DR

RNA interference (RNAi) is a promising but underexplored therapy for spinal cord injury, targeting genes involved in injury-related processes like inflammation and cell death.

## Contribution

This paper reviews RNAi's potential in SCI therapy, emphasizing novel tools like CRISPR-Cas13 and the need for translational research.

## Key findings

- RNAi can selectively silence genes and non-coding RNAs involved in SCI pathology.
- Combining RNAi with cell-based or biomaterial therapies may improve outcomes.
- Translational studies and systematic comparisons of RNAi targets are needed for clinical application.

## Abstract

Spinal cord injury (SCI) is a neurological condition often resulting in permanent motor and sensory deficits, for which effective treatments remain limited. RNA interference (RNAi) is a post-transcriptional mechanism of the downregulation of gene expression mediated by small interfering RNAs. RNAi has demonstrated therapeutic efficacy in various neurological disorders, positioning it as a promising yet underexplored therapeutic strategy for SCI. Here, we provide a focused overview of the key pathological processes in SCI, including primary mechanical injury and secondary cascades such as inflammation, mitochondrial dysfunction, excitotoxicity, oxidative stress, multiple forms of cell death, and others. The potential of RNAi to selectively silence genes implicated in these pathological processes, thereby enhancing neuroprotection and functional recovery, is highlighted. We point out that not only protein-coding genes, but non-coding RNAs (ncRNAs) are suitable targets for RNAi. Novel RNAi tools such as CRISPR-Cas13 might revolutionize the field and offer new opportunities for SCI therapy. However, despite all these promising findings, relevant translational studies of RNAi remain scarce. Challenges related to delivery methods, long-term efficacy, and cell-specific targeting must be addressed. Importantly, combining RNAi with other strategies such as cell- or biomaterial-based therapies may enhance therapeutic outcomes. Future investigations should prioritize systematic comparisons of RNAi targets and delivery systems, ideally at single-cell resolution and in different SCI models, to identify the most relevant molecular pathways for clinical translation. Overall, RNAi represents a compelling but still underdeveloped approach for SCI therapy, requiring continued refinement to reach clinical application.