TY  - JOUR
AU  - Wiora, Linus
AU  - Yuan, Qinggong
AU  - Hook, Sebastian
AU  - Kraft, Melanie
AU  - Björkhem, Ingemar
AU  - Ott, Michael
AU  - Hauser, Stefan
AU  - Schöls, Ludger
TI  - AAV8-based gene replacement therapy for hereditary spastic paraplegia type 5.
JO  - Molecular therapy / Methods & clinical development
VL  - 33
IS  - 3
SN  - 2329-0501
CY  - New York, NY
PB  - Nature Publishing Group
M1  - DZNE-2025-00924
SP  - 101531
PY  - 2025
AB  - 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.
KW  - AAV (Other)
KW  - CYP7B1 (Other)
KW  - SPG5 (Other)
KW  - cholesterol (Other)
KW  - gene therapy (Other)
KW  - hereditary spastic paraplegia (Other)
KW  - neurodegeneration (Other)
KW  - oxysterols (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40741602
C2  - pmc:PMC12309954
DO  - DOI:10.1016/j.omtm.2025.101531
UR  - https://pub.dzne.de/record/280246
ER  -