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Gene therapy corrects the neurological deficits of mice with sialidosis

Gene Therapy (2024)Cite this article

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Abstract

Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1−/−) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1−/− mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1−/− mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1−/− mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I.

After intracerebroventricular or facial vein injection of AAV vectors, NEU1 and PPCA are expressed together. PPCA-protected NEU1 is then sent to lysosomes, where β–Gal binds to this complex to form a multienzyme complex in order to execute its function.

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Fig. 1: Coexpression of PPCA improved the solubility of NEU1 in COS-1 cells.
Fig. 2: Expression of NEU1 and PPCA in Neu1−/− mice.
Fig. 3: Enzymatic analysis of Neu1−/− mice.
Fig. 4: Long-term correction of brain pathologies by gene therapy.
Fig. 5: Improvement of dorsal root ganglion pathologies by intracerebroventricular injection.
Fig. 6: Gene therapy improves the rotarod test performance of Neu1−/− mice.
Fig. 7: Gene therapy improves the grip strength of Neu1−/− mice.
Fig. 8: Gene therapy improves the body weight of Neu1−/− mice.

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Data availability

Data supporting the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This study is funded by the Sialidosis Research Fund of National Taiwan University Hospital (MS501) and by the Center for Frontier Medicine, National Taiwan University Hospital (111G-003). We thank the technical services provided by the “Transgenic Mouse Model Core Facility of the National Core Facility for Biopharmaceuticals, National Science and Technology Council, Taiwan” and the “Gene Knockout Mouse Core Laboratory of National Taiwan University Center of Genomic and Precision Medicine”. The authors also thank Dr. Yi-Ting Tsai, who interpreted the pathological features of the mice, and other scientists from the Laboratory Animal Center and the First Core Laboratory of National Taiwan University College of Medicine for their help in animal care and image data processing.

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Authors and Affiliations

  1. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan, ROC

    Wuh-Liang Hwu, Karine Chang, Hao-Chun Wang, Ni-Chung Lee & Yin-Hsiu Chien

  2. Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan, ROC

    Wuh-Liang Hwu, Yu-Han Liu, Ni-Chung Lee & Yin-Hsiu Chien

  3. Precision Medical Center, China Medical University Hospital, Taichung City, Taiwan, ROC

    Wuh-Liang Hwu

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Hwu, WL., Chang, K., Liu, YH. et al. Gene therapy corrects the neurological deficits of mice with sialidosis. Gene Ther (2024). https://doi.org/10.1038/s41434-024-00443-3

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