Introduction and Objective: We recently reported the development of the first dose adjustable lipid nanoparticle (LNP) gene delivery platform with high durability and functional up/down-titration. Incretin therapies are effective in treating type 2 diabetes (T2D) but require frequent dosing and are plagued by high discontinuation rates. To overcome these challenges, we aimed to develop an adjustable-dose incretin gene therapy using LNP and evaluate its efficacy in a mouse model of T2D.
Methods: C57BL6 mice were fed either low-fat or high-fat diet, followed by low-dose streptozotocin (40mg/kg BW) to induce T2D. T2D mice were treated subcutaneously with LNP-GLP1, LNP-EX4 or vehicle. Animals were followed for 14 weeks. Body weight, GTT and ITT tests were measured.
Results: LNP-GLP1 and EX4 treatment produced 20% and 14% weight loss at 4 weeks relative to vehicle, 37% and 38% reduction in fasting glucose, 29% and 26% reduction in area under the curve of GTT, and 25% and 22% reduction in ITT, respectively (p≤0.05). The transgene was localized to the injection site with no detection in the liver, heart, spleen, or kidney. There were no significant changes in systemic markers of inflammation (IL6 and TNFα) or liver damage (ALP).
Conclusion: Our study demonstrates the ability of a novel incretin gene therapy delivered by LNP to induce weight loss, improve insulin resistance, and glycemic control in T2D.
J. Lourie: None. A. Goraltchouk: Board Member; Remedium Bio, Inc. Employee; Remedium Bio, Inc. A. Fujishiro: None. N. Berger: None. H.G. Rosen: None. J. Hollander: Employee; Remedium Bio, Inc. Stock/Shareholder; Remedium Bio, Inc. F. Luppino: None. A. Seregin: Employee; Remedium Bio. K. Zou: Research Support; Remedium Bio.
National Science Foundation (#2240683)
