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Efficiency of PGK1 proteins delivered to the brain via a liposomal system through intranasal route administration for the treatment of spinocerebellar ataxia type 3

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Abstract

A patient-friendly and efficient treatment method for patients with spinocerebellar ataxia type 3 (SCA3) was provided through a nose-to-brain liposomal system. Initially, PGK1 was overexpressed in HEK 293-84Q-GFP diseased cells (HEK 293-84Q-GFP-PGK1 cells) to confirm its effect on the diseased protein polyQ. A decrease in polyQ expression was demonstrated in HEK 293-84Q-GFP-PGK1 cells compared to HEK 293-84Q-GFP parental cells. Subsequently, PGK1 was encapsulated in a liposomal system to evaluate its therapeutic efficiency in SCA3. The optimized liposomes exhibited a significantly enhanced positive charge, facilitating efficient intracellular protein delivery to the cells. The proteins were encapsulated within the liposomes using an optimized method involving a combination of heat shock and sonication. The liposomal system was further demonstrated to be deliverable to the brain via intranasal administration. PGK1/liposomes were intranasally delivered to SCA3 mice, which subsequently exhibited an amelioration of motor impairment, as assessed via the accelerated rotarod test. Additionally, fewer shrunken morphology Purkinje cells and a reduction in polyQ expression were observed in SCA3 mice that received PGK1/liposomes but not in the untreated, liposome-only, or PGK1-only groups. This study provides a non-invasive route for protein delivery and greater delivery efficiency via the liposomal system for treating neurodegenerative diseases.

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The raw/processed data required to reproduce these findings cannot be shared at this time due to part of an ongoing study.

Abbreviations

SCA3:

Spinocerebellar ataxia type 3

polyQ:

Polyglutamine

PGK1:

Phosphoglycerate kinase 1

MJD:

Machado–Joseph disease

FDA:

Food and Drug Administration

PET:

Positron emission tomography

FDG:

[18F]-2-Fluoro-2-deoxy-D-glucose

TCA:

Tricarboxylic acid

ALS:

Amyotrophic lateral sclerosis (ALS)

PD:

Parkinson’s disease

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Acknowledgements

We thank the Electron Microscopy Laboratory of Tzu Chi University for their assistance with the TEM support.

Funding

This work was supported by the Ministry of Science and Technology, Taiwan, R.O.C. (MOST-111-2221-E-303-001); the National Science and Technology Council, Taiwan, R.O.C. (NSTC-112-2221-E-303-002); and Hualien Tzu Chi hospital, Buddhist Tzu Chi Medical Foundation, 509 Taiwan, Republic of China (IMAR-110-01-18).

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Author notes

  1. Shinn-Zong Lin

    Present address: Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, 707, Sec.3, Chung-Yang Rd., 970, R.O.C, Hualien, Taiwan

Authors and Affiliations

  1. Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, 707, Sec.3, Chung-Yang Rd., 970, R.O.C, Hualien, Taiwan

    Yu-Shuan Chen, Zhen-Xiang Hong, Yi-Tung Lin, En-CI Tsao, Pei-Yu Chen, Ching-Ann Liu & Horng-Jyh Harn

  2. Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

    Yu-Shuan Chen & Ching-Ann Liu

  3. Tzu Chi University of Science and Technology, Hualien, Taiwan

    Yu-Shuan Chen

  4. Department of Pathology, Hualien Tzu Chi Hospital, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

    Horng-Jyh Harn

  5. Department of Life Science, National Dong Hwa University, Hualien, Taiwan

    Tzyy-Wen Chiou

  6. Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

    Shinn-Zong Lin

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Contributions

Y-SC designed the experiments, and Y-SC, Z-XH, Y-TL, E-CT, P-YC, and C-AL performed the experiments. Y-SC, Z-XH, Y-TL, E-CT, P-YC, and C-AL contributed to data compilation and paper preparation. Y-SC, Z-XH, Y-TL, E-CT, P-YC, C-AL, H-JH, T-WC, and S-ZL provided critical feedback on the study and contributed to the preparation of the paper. Y-SC, H-JH, T-WC, and S-ZL provided a resource of papers. Y-SC and S-ZL provided project management for papers. All authors read and approved the final manuscript.

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Correspondence to Yu-Shuan Chen or Shinn-Zong Lin.

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Chen, YS., Hong, ZX., Lin, YT. et al. Efficiency of PGK1 proteins delivered to the brain via a liposomal system through intranasal route administration for the treatment of spinocerebellar ataxia type 3. Drug Deliv. and Transl. Res. (2023). https://doi.org/10.1007/s13346-023-01498-2

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