Systemically delivered lipid nanoparticle-mRNA encoding lysosomal acid β-glucosidase restores the enzyme deficiency in a murine Gaucher disease model.

Gaucher disease (GD) is a rare genetically inherited illness caused by loss of lysosomal acid β-glucosidase (β-GCase) that leads to progressive accumulation of substrates, sphingolipid glucosylceramide (GL1) and glucosylsphingosine (lyso-GL1). The protein-based enzyme replacement therapy (ERT) requires frequent dosing due to short drug half-life causing challenges in long-term patient compliance. JCXH-301 is a lipid nanoparticle (LNP) encapsulated messenger RNA (mRNA) encoding β-GCase. Intravenous administration of JCXH-301 delivered the target mRNA to various tissues in mice with intracellular expression of β-GCase predominantly in macrophages and dendritic cells in the spleen and bone marrow. In GBA1 D427V homozygous mice treated with JCXH-301, the dose-dependent in vivo production of functional β-GCase resulted in reduction of serum lyso-GL1, a key biomarker of GD. The therapeutic effect of JCXH-301 was sustained for a duration significantly longer than that of protein-based ERT Cerezyme. JCXH-301 administration induced minimal pro-inflammatory cytokines in the liver and spleen. Taken together, these results provide proof-of-concept for using LNP-delivered mRNA as a new drug modality to restore the β-GCase genetic deficiency for GD treatment.