Neuropathic pain remains a significant clinical challenge due to the limited efficacy and sustainability of existing pharmacological treatments, underscoring the urgent need for mechanism-based therapeutic strategies. In recent years, gene-targeted interventions have emerged as promising modalities capable of modulating key molecular pathways implicated in chronic pain. Approaches such as antisense oligonucleotides and RNA interference have demonstrated encouraging preclinical results by selectively downregulating pain-associated genes. Based on these developments, genome-editing technologies—particularly the clustered regularly interspaced short palindromic repeats (CRISPR) system—have enabled more precise and long-lasting modifications at both the DNA and RNA levels. This review highlights how CRISPR-based approaches in addressing the critical issues of specificity and long-term efficacy in pain gene therapy and exploring the functional roles of key gene targets and regulatory elements. Although challenges such as off-target activity and immunogenic responses remain, growing preclinical evidence supports the feasibility of CRISPR-based approaches in neuropathic pain. Collectively, these developments position CRISPR as a transformative tool to innovate the standard care for persistent pain syndromes and contribute to broader biomedical and pharmaceutical developments through continued refinement of targeting strategies and safety profiles.
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Intervertebral disc degeneration is the primary cause of back pain and associated with neurological disorders including radiculopathy, myelopathy, and paralysis. The currently available surgical treatments predominantly include the excision of pathological discs, resulting in the function loss, immobilization, and potential additional complications due to the altered biomechanics. Gene therapy approach involves gene transfer into cells, affects RNA and protein synthesis of the encoded genes in the recipient cells, and facilitates biological treatment. Relatively long-exerting therapeutic effects by gene therapy are potentially advantageous to treat slow progressive degenerative disc disease. In gene therapy, the delivery method and selection of target gene(s) are essential. Although gene therapy was first mediated by viral vectors, technological progress has enabled to apply nonviral vectors and polyplex micelles for the disc. While RNA interference successfully provides specific downregulation of multiple genes in the disc, clustered regularly interspaced short palindromic repeats (CRISPR) system has increased attention to alter the process of intervertebral disc degeneration. Then, more recent findings of our studies have suggested autophagy, the intracellular self-digestion, and recycling system under the negative regulation by the mammalian target of rapamycin (mTOR), as a gene therapy target in the disc. Here we briefly review backgrounds and applications of gene therapy for the disc, introducing strategies of autophagy and mTOR signaling modulation through selective RNA interference.
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