Objective: To develop lipid nanoparticles with high efficiency and specificity to introduce mRNA into oligodendrocytes. To denmonstrate the potential therapy of Krabbe disease as one of the applications.

Background: Oligodendrocytes are implicated in various diseases such as congenital disorders and multiple system atrophy (MSA). However, conventional viral vectors are not efficient in transfecting oligodendrocytes. In this study, we introduced mRNAs into oligodendrocytes with high efficiency and specificity using LUNAR® lipid nanoparticles (LNPs).

Method: We treated primary cell cultures with LUNAR®-EGFP mRNA and injected LUNAR®-EGFP mRNA into the striatum of mice. Immunofluorescence of neuronal, astrocytes, oligodendrocytes, and microglial markers was performed in the mice brain samples. We evaluated the uptake of LUNAR®-EGFP mRNA in cultured cells knocked down by LDLR, VLDLR, and ApoER2 siRNA. Furthermore, we administered LUNAR®-GALC mRNA to twitcher mice – a mouse model of Krabbe disease characterized by GALC deficiency and subsequent oligodendrocyte damage – and assessed motor function and survival after treatment.

Results: EGFP induced by LUNAR®- EGFP mRNA was widely expressed in oligodendrocytes with high efficiency and specificity. The uptake of LUNAR® LNPs occurring via low-density lipoprotein receptors in the presence of apolipoprotein E. A single dose of LUNAR-human GALC mRNA significantly improved phenotypes and survival of twitcher mice.

Conclusion: This cell-specific mRNA delivery approach using LUNAR® demonstrates remarkable potential for the treatment of Krabbe disease, and other oligodendrocytes-related neurological disorders including MSA.

References: 1. A lipid nanoparticle-based oligodendrocyte-specific mRNA therapy. Mol Ther Nucleic Acids. 2024 Nov 5;35(4):102380. doi: 10.1016/j.omtn.2024.102380.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/oligodendrocyte-specific-mrna-therapy-with-lipid-nanoparticles/