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Intravenous Administration of an AAV9 Vector Ubiquitously Expressing C1orf194 Gene Improved CMT-Like Neuropathy in C1orf194-/- Mice

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Neurotherapeutics

Abstract

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, is a group of rare genetically heterogenous diseases characterized by progressive muscle weakness and atrophy, along with sensory deficits. Despite extensive pre-clinical and clinical research, no FDA-approved therapy is available for any CMT type. We previously identified C1ORF194, a novel causative gene for CMT, and found that both C1orf194 knock-in (I121N) and knockout mice developed clinical phenotypes similar to those in patients with CMT. Encouraging results of adeno-associated virus (AAV)-mediated gene therapy for spinal muscular atrophy have stimulated the use of AAVs as vehicles for CMT gene therapy. Here, we present a gene therapy approach to restore C1orf194 expression in a knockout background. We used C1orf194-/- mice treated with AAV serotype 9 (AAV9) vector carrying a codon-optimized WT human C1ORF194 cDNA whose expression was driven by a ubiquitously expressed chicken β-actin promoter with a CMV enhancer. Our preclinical evaluation demonstrated the efficacy of AAV-mediated gene therapy in improving sensory and motor abilities, thus achieving largely normal gross motor performance and minimal signs of neuropathy, on the basis of neurophysiological and histopathological evaluation in C1orf194-/- mice administered AAV gene therapy. Our findings advance the techniques for delivering therapeutic interventions to individuals with CMT.

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Acknowledgements

The authors thank the patients for supporting previous research that facilitated the generation of this manuscript. We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (32170617 and 31970558), National Key S&T Special Projects (2021YFC100530 and 2022YFC2703303), and Natural Science Foundation of Guangdong Province of China (2022A1515012621).

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Authors and Affiliations

  1. Department of Medical Genetics, Experimental Education/Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Zongrui Shen, Meiyi Li, Fei He, Cheng Huang, Yingchun Zheng, Zhikui Wang, Shunfei Ma, Li Chen & Fu Xiong

  2. Department of Neurology, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Hui Zheng

  3. Division of Translational Neuroscience in Schizophrenia, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Zhengshan Liu

  4. Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, Guangdong, China

    Fu Xiong

  5. Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Fu Xiong

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  1. Zongrui Shen
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Shen, Z., Li, M., He, F. et al. Intravenous Administration of an AAV9 Vector Ubiquitously Expressing C1orf194 Gene Improved CMT-Like Neuropathy in C1orf194-/- Mice. Neurotherapeutics 20, 1835–1846 (2023). https://doi.org/10.1007/s13311-023-01429-6

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