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

Gene Therapy (2025)Cite this article

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Abstract

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.

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Fig. 1: Structure and characterization of JCXH-301m.
Fig. 2: Distribution of JCXH-301m after i.v. administration in naïve mice.
Fig. 3: Expression of β-GCase in GBA1 D427V mice after i.v. administration of JCXH-301m or Cerezyme.
Fig. 4: Enzymatic activity of β-GCase in GBA1 D427V mutant mice after i.v. administration of JCXH-301m or Cerezyme.
Fig. 5: Effect of multiple injections of JCXH-301m or Cerezyme in GBA1 D427V mutant mice.
Fig. 6: The human β-GCase protein level and enzymatic activity in GBA1 D427V mutant mice after i.v. injection of JCXH-301.

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Data availability

The sequences generated in this study are available in the NCBI database (Accession Gene ID. 2629 and 14466). The other data related to this study are available from the corresponding author upon request, with the permission of Immorna Biotechnology/Immorna Biotherapeutics.

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Acknowledgements

We thank Shanghai Model Organisms Center Inc. and Ms. Dongli Liang of Shanghai Jiaotong University for their expert assistance in mouse experiments. We thank Mr. Ji Xu and Ms. Yanqi Su for the logistical support.

Funding

The study was fully funded by Immorna Biotechnology/Immorna Biotherapeutics.

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Authors and Affiliations

  1. Immorna (Shanghai) Biotechnology, Co. Ltd., Shanghai, China

    Yuanqing Liu, Shasha Wang, Yanni Chen & Xiaojiang Quan

  2. Immorna (Hangzhou) Biotechnology, Co. Ltd., Hangzhou, Zhejiang, China

    Zhang Zhang, Zhijun Guo & Zihao Wang

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Contributions

Z.W., Z.G., S.W., Y.C., and Y.L. developed the concept and designed the studies. S.W. and Z.Z performed the experiments and curated the data. S.W., Z.Z., and Y.C. analyzed the data. S.W., Y.C., X.Q., and Y.L. wrote the manuscript. All the authors reviewed the manuscript and agreed this version to be published.

Corresponding author

Correspondence to Yuanqing Liu.

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Competing interests

All authors are employees of Immorna Biotechnology/Immorna Biotherapeutics. Z.W., Y. L., and Z. G. are inventors to the Chinese patent CN118903476B.

Ethics approval statement

All animal experiments were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals and relevant Chinese laws and regulations. All animal use adhered to the IACUC guidelines for animal ethics and welfare. The in vivo experiment protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Jiaotong University, China (authorization number: A2022044), and Shanghai Model Organisms Center, Inc., China (authorization number: No. 2020-0047).

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Liu, Y., Wang, S., Chen, Y. et al. Systemically delivered lipid nanoparticle-mRNA encoding lysosomal acid β-glucosidase restores the enzyme deficiency in a murine Gaucher disease model. Gene Ther (2025). https://doi.org/10.1038/s41434-025-00549-2

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