Liposome-targeted recombinant human acid sphingomyelinase: Production, formulation, and in vitro evaluation

Mohammed H. Aldosari, Robert P. de Vries, Lucia R. Rodriguez, Nienke A. Hesen, Nataliia Beztsinna, André B.P. van Kuilenburg, Carla E.M. Hollak, Huub Schellekens, Enrico Mastrobattista*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Niemann-Pick disease type B is a hereditary rare condition caused by deficiency of the acid sphingomyelinase (ASM) that is needed for lysosomal hydrolysis of sphingomyelin to ceramide and phosphocholine. This deficiency leads to a massive accumulation of sphingomyelin in cells throughout the body, predominantly in the liver, spleen and lungs. Currently, there is no effective treatment available. Olipudase alfa (recombinant human acid sphingomyelinase; rhASM) is an investigational drug that has shown promising results. However, dose-dependent toxicity was observed in mice upon the intravenous administration of rhASM, potentially due to the systemic release of ceramide upon the extracellular degradation of sphingomyelin by rhASM. Using a nanocarrier to deliver the rhASM to cells could improve the therapeutic window by shielding the rhASM to prevent the off-target degradation of sphingomyelin. For this aim, we recombinantly expressed hASM in human cells and loaded it into different liposomal formulations at a drug-to-lipid ratio of 4% (w/w). Among four formulations, the liposomal rhASM formulation with the composition DPPC:DOPS:BMP:CHOL:DiD (59:20:10:10:1 mol%) was selected because of its superiority concerning the encapsulation efficiency of rhASM (21%) and cellular uptake by fibroblasts and macrophages. The selected liposomal rhASM formulation significantly reduced the accumulated lyso-sphingomyelin in NPD-B fibroblasts by 71%, part of this effect was stimulated by the used lipids, compared to 55% when using the free rhASM enzyme. More importantly, the undesired extracellular degradation of sphingomyelin was reduced when using the selected liposomal rhASM by 61% relative to the free rhASM. The presented in vitro data indicate that the liposomal rhASM is effective and may provide a safer intervention than free rhASM.

Original languageEnglish
Pages (from-to)185-195
Number of pages11
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume137
DOIs
Publication statusPublished - 1 Apr 2019

Funding

This work was funded by Saudi Food and Drug Authority (Riyadh, Saudi Arabia) via a PhD scholarship to Mohammed H. Aldosari. R.P. de Vries is funded by a VENI grant from the Netherlands Organization for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

  • Acid sphingomyelinase
  • Enzyme replacement therapy
  • Liposome
  • Lysosomal storage disease
  • Niemann-Pick disease
  • Rare disease

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