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Golgi-endosome transport mediated by M6PR facilitates release of antisense oligonucleotides from endosomes. | LitMetric

AI Article Synopsis

  • The study investigates how phosphorothioate antisense oligonucleotides (PS-ASOs) are transported from late endosomes (LEs) for effective drug delivery, focusing on the roles of proteins GCC2 and M6PR.
  • Researchers found that a decrease in GCC2 or M6PR levels hampers PS-ASO release from endosomes and reduces their activity in human cells.
  • The results suggest that GCC2 and M6PR work together in a pathway to aid PS-ASO release, with protein interactions influenced by PS modifications, and this mechanism is consistent in both human and mouse cells.

Article Abstract

Release of phosphorothioate antisense oligonucleotides (PS-ASOs) from late endosomes (LEs) is a rate-limiting step and a poorly defined process for productive intracellular ASO drug delivery. Here, we examined the role of Golgi-endosome transport, specifically M6PR shuttling mediated by GCC2, in PS-ASO trafficking and activity. We found that reduction in cellular levels of GCC2 or M6PR impaired PS-ASO release from endosomes and decreased PS-ASO activity in human cells. GCC2 relocated to LEs upon PS-ASO treatment, and M6PR also co-localized with PS-ASOs in LEs or on LE membranes. These proteins act through the same pathway to influence PS-ASO activity, with GCC2 action preceding that of M6PR. Our data indicate that M6PR binds PS-ASOs and facilitates their vesicular escape. The co-localization of M6PR and of GCC2 with ASOs is influenced by the PS modifications, which have been shown to enhance the affinity of ASOs for proteins, suggesting that localization of these proteins to LEs is mediated by ASO-protein interactions. Reduction of M6PR levels also decreased PS-ASO activity in mouse cells and in livers of mice treated subcutaneously with PS-ASO, indicating a conserved mechanism. Together, these results demonstrate that the transport machinery between LE and Golgi facilitates PS-ASO release.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026651PMC
http://dx.doi.org/10.1093/nar/gkz1171DOI Listing

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