Future science OA · 2026
Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy.
СтатьяНазвание и аннотация: Перевод в очереди
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Kerneis Fabienne, Jay Christopher M, Rao Donald, Winchester Jeremy, Nemunaitis Alexander, Nemunaitis Emily, Bognar Ernest, Wallraven Gladice, Stanbery Laura, Walter Adam, Sarshar Sep, Nemunaitis John
Аннотация
AIMS: GNE myopathy is a heredity disease of unmet medical need associated with progressive skeletal muscle wasting, atrophy and weakness caused by mutations in the GNE gene. GNE plays a pivotal role in sialic acid production. Sialic acid is a critical part of glycoprotein, ganglioside and glycolipid cell-cell interaction which is necessary for normal skeletal muscle function. Previously we demonstrated safety and efficacy of the GNEwt gene lipoplex in one patient.
METHODS: We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle.
RESULTS: We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection.
CONCLUSION: These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy.
METHODS: We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle.
RESULTS: We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection.
CONCLUSION: These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy.