Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

Translational Neurodegeneration

Guenther Staffler¹  Sabine Schmidhuber¹  Gergana Galabova²  Armin Giese³  Nadia Stefanova⁴  Miguel Lemos⁴  Violetta Refolo⁴  Serena Venezia⁴  Antonio Heras-Garvin⁴  Gregor Karl Wenning⁴  Sergey Ryazanov⁵  Andrei Leonov⁵  Christian Griesinger⁵ 

[1] AFFIRIS AG, Vienna, Austria;AFFIRIS AG, Vienna, Austria;Present Address: Origenis GmbH, Munich, Germany;Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany;Division of Neurobiology, Department of Neurology, Innsbruck Medical University, 6020, Innsbruck, Austria;Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;

关键词: α-Synuclein;    Immunotherapy;    Oligomer modulation;    Target engagement;    Substantia nigra;    Microglia;   

DOI  :  10.1186/s40035-020-00217-y

来源: Springer

【 摘 要 】

BackgroundMisfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson’s disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. Here we aimed to analyze the therapeutic efficacy of PD03, a new AFFITOPE® immunotherapy approach, either alone or in combination with Anle138b, in a PLP-α-syn mouse model.MethodsThe PLP-α-syn mice were treated with PD03 immunotherapy, Anle138b, or a combination of two. Five months after study initiation, the mice underwent behavioral testing and were sacrificed for neuropathological analysis. The treatment groups were compared to the vehicle group with regard to motor performance, nigral neuronal loss, microglial activation and α-synuclein pathology.ResultsThe PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial activation. The combined therapy with Anle138b and PD03 resulted in lower IgG binding in the brain as compared to the single immunotherapy with PD03.ConclusionsPD03 and Anle138b can selectively target oligomeric α-synuclein, resulting in attenuation of neurodegeneration in the PLP-α-syn mice. Both approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.

【 授权许可】

CC BY