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@ARTICLE{Wiora:280246,
      author       = {Wiora, Linus and Yuan, Qinggong and Hook, Sebastian and
                      Kraft, Melanie and Björkhem, Ingemar and Ott, Michael and
                      Hauser, Stefan and Schöls, Ludger},
      title        = {{AAV}8-based gene replacement therapy for hereditary
                      spastic paraplegia type 5.},
      journal      = {Molecular therapy / Methods $\&$ clinical development},
      volume       = {33},
      number       = {3},
      issn         = {2329-0501},
      address      = {New York, NY},
      publisher    = {Nature Publishing Group},
      reportid     = {DZNE-2025-00924},
      pages        = {101531},
      year         = {2025},
      abstract     = {Hereditary spastic paraplegia type 5 (SPG5) is an autosomal
                      recessive neurological disorder caused by mutations in the
                      CYP7B1 gene, which encodes cholesterol 7α-hydroxylase, an
                      essential enzyme in cholesterol metabolism. These mutations
                      lead to elevated levels of 25- and 27-hydroxycholesterol,
                      oxysterols known to be neurotoxic and blood-brain-barrier
                      permeable. Their accumulation contributes significantly to
                      SPG5 pathogenesis, resulting in spastic gait disturbance and
                      severely impaired quality of life. Using a Cyp7b1-/- mouse
                      model that mirrors the metabolic phenotype of SPG5, we
                      developed a gene therapy approach to correct oxysterol
                      imbalance. We designed an AAV8-TTR-hCYP7B1 vector to deliver
                      the CYP7B1 gene specifically to the liver. Following
                      intravenous administration, oxysterol levels in blood and
                      liver were rapidly normalized, even at low doses (1E10),
                      with no observed toxicity at the highest tested dose (1E11).
                      Despite these promising peripheral results, oxysterol levels
                      in the brain, particularly 27-hydroxycholesterol, remained
                      only partially corrected six weeks post-treatment. Our
                      findings suggest that while liver-targeted gene therapy is
                      effective at restoring peripheral cholesterol metabolism, a
                      successful therapeutic strategy for SPG5 must also address
                      central nervous system involvement. We conclude that
                      successful treatment of SPG5 would require a novel gene
                      therapeutic approach that also targets the CNS.},
      keywords     = {AAV (Other) / CYP7B1 (Other) / SPG5 (Other) / cholesterol
                      (Other) / gene therapy (Other) / hereditary spastic
                      paraplegia (Other) / neurodegeneration (Other) / oxysterols
                      (Other)},
      cin          = {AG Schöls / AG Hauser},
      ddc          = {610},
      cid          = {I:(DE-2719)5000005 / I:(DE-2719)1210016},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40741602},
      pmc          = {pmc:PMC12309954},
      doi          = {10.1016/j.omtm.2025.101531},
      url          = {https://pub.dzne.de/record/280246},
}