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Effect of acid sphingomyelinase deficiency in type A Niemann-Pick disease on the transport of therapeutic nanocarriers across the blood–brain barrier

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Abstract

ASM deficiency in Niemann-Pick disease type A results in aberrant cellular accumulation of sphingomyelin, neuroinflammation, neurodegeneration, and early death. There is no available treatment because enzyme replacement therapy cannot surmount the blood–brain barrier (BBB). Nanocarriers (NCs) targeted across the BBB via transcytosis might help; yet, whether ASM deficiency alters transcytosis remains poorly characterized. We investigated this using model NCs targeted to intracellular adhesion molecule-1 (ICAM-1), transferrin receptor (TfR), or plasmalemma vesicle-associated protein-1 (PV1) in ASM-normal vs. ASM-deficient BBB models. Disease differentially changed the expression of all three targets, with ICAM-1 becoming the highest. Apical binding and uptake of anti-TfR NCs and anti-PV1 NCs were unaffected by disease, while anti-ICAM-1 NCs had increased apical binding and decreased uptake rate, resulting in unchanged intracellular NCs. Additionally, anti-ICAM-1 NCs underwent basolateral reuptake after transcytosis, whose rate was decreased by disease, as for apical uptake. Consequently, disease increased the effective transcytosis rate for anti-ICAM-1 NCs. Increased transcytosis was also observed for anti-PV1 NCs, while anti-TfR NCs remained unaffected. A fraction of each formulation trafficked to endothelial lysosomes. This was decreased in disease for anti-ICAM-1 NCs and anti-PV1 NCs, agreeing with opposite transcytosis changes, while it increased for anti-TfR NCs. Overall, these variations in receptor expression and NC transport resulted in anti-ICAM-1 NCs displaying the highest absolute transcytosis in the disease condition. Furthermore, these results revealed that ASM deficiency can differently alter these processes depending on the particular target, for which this type of study is key to guide the design of therapeutic NCs.

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Acknowledgements

BioRender.com was used for the creation of the graphical abstract and Fig. 10.

Funding

SM: RTI2018-101034-B-I00 from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and “ERDF A way of making Europe,” and CERCA Program (Generalitat de Catalunya). ML: INPhINIT Predoctoral Fellowship (LCF/BQ/DI18/11660018) funded by Fundación La Caixa and Horizon 2020 Marie Sklodowska-Curie (grant 713673). MP: FPI PRE2021-098133 funded by the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and “ESF Investing in your future.”

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  1. Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology, Barcelona, Spain

    Maximilian Loeck, Marina Placci & Silvia Muro

  2. Institution of Catalonia for Research and Advanced Studies (ICREA), Barcelona, Spain

    Silvia Muro

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  1. Maximilian Loeck
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M.L. performed and analyzed majority of the experiments, drafted the manuscript, and prepared figures. M.P. performed and analyzed the flow cytometry experiment, prepared respective figure, and helped edit the manuscript. S.M conceptualized and directed the investigation, secured funding, helped plan experiments and interpret results, and helped write and edit the text and figures.

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Correspondence to Silvia Muro.

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Loeck, M., Placci, M. & Muro, S. Effect of acid sphingomyelinase deficiency in type A Niemann-Pick disease on the transport of therapeutic nanocarriers across the blood–brain barrier. Drug Deliv. and Transl. Res. 13, 3077–3093 (2023). https://doi.org/10.1007/s13346-023-01374-z

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