SINEUP-Mediated Overexpression of Endogenous α-Amylase as a Therapeutic Approach in Lafora Disease

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Background/Objectives: Lafora disease is a fatal and progressive neurodegenerative disorder characterized by the accumulation of insoluble polyglucosan inclusions, known as Lafora bodies, due to impaired glycogen metabolism. Therapeutic strategies aimed at reducing intracellular glycogen accumulation represent a promising approach to mitigating disease progression. This study aimed to evaluate the feasibility of promoting Lafora body degradation by increasing the protein levels of human pancreatic amylase, a glycogen-degrading enzyme, through the SINEUP approach. Methods: Two SINEUP constructs specifically targeting human pancreatic amylase were designed and tested in continuous tumor-derived cell lines of central nervous system origin, as well as in primary fibroblasts obtained from a patient with Lafora disease. Human pancreatic amylase protein and mRNA levels were assessed to determine the specificity of SINEUP-mediated regulation. Enzymatic activity assays were performed to evaluate functional protein upregulation, and intracellular glycogen content was measured in patient-derived fibroblasts. Results: Both SINEUP constructs significantly increased human pancreatic amylase protein expression without affecting mRNA levels, confirming a post-transcriptional mechanism of action. The elevated protein levels were associated with a significant increase in enzymatic activity. In primary fibroblasts derived from a Lafora disease patient, enhanced amylase expression correlated with a marked reduction in intracellular glycogen content. Conclusions: These findings provide proof of concept that SINEUP-mediated upregulation of glycogen-degrading enzymes may represent a viable therapeutic strategy to counteract Lafora body accumulation. Further studies are warranted to assess the efficacy, safety, and translational potential of this approach, particularly in relevant animal models of Lafora disease.

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