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@ARTICLE{Dchs:258682,
      author       = {Düchs, Matthias and Blazevic, Dragica and Rechtsteiner,
                      Philipp and Kenny, Cynthia and Lamla, Thorsten and Low,
                      Sarah and Savistchenko, Jimmy and Neumann, Manuela and
                      Melki, Ronald and Schönberger, Tanja and Stierstorfer,
                      Birgit and Wyatt, David and Igney, Frederik and Ciossek,
                      Thomas},
      title        = {{AAV}-mediated expression of a new conformational
                      anti-aggregated α-synuclein antibody prolongs survival in a
                      genetic model of α-synucleinopathies.},
      journal      = {npj Parkinson's Disease},
      volume       = {9},
      number       = {1},
      issn         = {2373-8057},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DZNE-2023-00655},
      pages        = {91},
      year         = {2023},
      abstract     = {Prion-like transmission of pathology in
                      α-synucleinopathies like Parkinson's disease or multiple
                      system atrophy is increasingly recognized as one potential
                      mechanism to address disease progression. Active and passive
                      immunotherapies targeting insoluble, aggregated α-synuclein
                      are already being actively explored in the clinic with mixed
                      outcomes so far. Here, we report the identification of
                      306C7B3, a highly selective, aggregate-specific α-synuclein
                      antibody with picomolar affinity devoid of binding to the
                      monomeric, physiologic protein. 306C7B3 binding is
                      Ser129-phosphorylation independent and shows high affinity
                      to several different aggregated α-synuclein polymorphs,
                      increasing the likelihood that it can also bind to the
                      pathological seeds assumed to drive disease progression in
                      patients. In support of this, highly selective binding to
                      pathological aggregates in postmortem brains of MSA patients
                      was demonstrated, with no staining in samples from other
                      human neurodegenerative diseases. To achieve CNS exposure of
                      306C7B3, an adeno-associated virus (AAV) based approach
                      driving expression of the secreted antibody within the brain
                      of (Thy-1)-[A30P]-hα-synuclein mice was used. Widespread
                      central transduction after intrastriatal inoculation was
                      ensured by using the AAV2HBKO serotype, with transduction
                      being spread to areas far away from the inoculation site.
                      Treatment of (Thy-1)-[A30P]-hα-synuclein mice at the age of
                      12 months demonstrated significantly increased survival,
                      with 306C7B3 concentration reaching 3.9 nM in the
                      cerebrospinal fluid. These results suggest that AAV-mediated
                      expression of 306C7B3, targeting extracellular, presumably
                      disease-propagating aggregates of α-synuclein, has great
                      potential as a disease-modifying therapy for
                      α-synucleinopathies as it ensures CNS exposure of the
                      antibody, thereby mitigating the selective permeability of
                      the blood-brain barrier.},
      cin          = {AG Neumann},
      ddc          = {610},
      cid          = {I:(DE-2719)1210003},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37322068},
      pmc          = {pmc:PMC10272115},
      doi          = {10.1038/s41531-023-00542-9},
      url          = {https://pub.dzne.de/record/258682},
}