2. Academic Validation
  3. Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model

Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model

  • Cell. 2023 Oct 30:S0092-8674(23)01086-3. doi: 10.1016/j.cell.2023.10.004.
Yefei Chen 1,  Zexuan Hong 2,  Jingyi Wang 3,  Kunlin Liu 4,  Jing Liu 2,  Jianbang Lin 3,  Shijing Feng 1,  Tianhui Zhang 5,  Liang Shan 1,  Taian Liu 1,  Pinyue Guo 1,  Yunping Lin 1,  Tian Li 1,  Qian Chen 6,  Xiaodan Jiang 7,  Anan Li 8,  Xiang Li 3,  Yuantao Li 9,  Jonathan J Wilde 10,  Jin Bao 11,  Ji Dai 12,  Zhonghua Lu 13
Affiliations

Affiliations

  • 1 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 2 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Department of Anesthesiology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518027, China.
  • 3 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
  • 5 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou 221004, China.
  • 6 University of Chinese Academy of Sciences, Beijing 100049, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 7 Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
  • 8 Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou 221004, China.
  • 9 Department of Anesthesiology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518027, China; Biomedical Research Institute, Hubei University of Medicine, Shiyan 442000, China.
  • 10 Emugen Therapeutics LLC, Woburn, MA 01801, USA.
  • 11 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Biomedical Imaging Science and System Key Laboratory, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: [email protected].
  • 12 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: [email protected].
  • 13 Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Biomedical Imaging Science and System Key Laboratory, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: [email protected].
PMID: 37922901 DOI: 10.1016/j.cell.2023.10.004
Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or Dopamine Receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.

Keywords

Parkinson’s disease; chemogenetics; gene therapy; nonhuman primate; retrograde AAV; targeted circuit manipulation.

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