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Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy

Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed...

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Main Authors: Lauer, Arne (Author) , Speroni, Samantha L. (Author) , Choi, Myoung (Author) , Da, Xiao (Author) , Duncan, Christine (Author) , McCarthy, Siobhan (Author) , Krishnan, Vijai (Author) , Lusk, Cole A. (Author) , Rohde, David (Author) , Hansen, Mikkel Bo (Author) , Kalpathy-Cramer, Jayashree (Author) , Loes, Daniel J. (Author) , Caruso, Paul A. (Author) , Williams, David A. (Author) , Mouridsen, Kim (Author) , Emblem, Kyrre E. (Author) , Eichler, Florian S. (Author) , Musolino, Patricia L. (Author)
Format: Article (Journal)
Language:English
Published: 05 April 2023
In: Nature Communications
Year: 2023, Volume: 14, Pages: 1-10
ISSN:2041-1723
DOI:10.1038/s41467-023-37262-w
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-023-37262-w
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-023-37262-w
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Author Notes:Arne Lauer, Samantha L. Speroni, Myoung Choi, Xiao Da, Christine Duncan, Siobhan McCarthy, Vijai Krishnan, Cole A. Lusk, David Rohde, Mikkel Bo Hansen, Jayashree Kalpathy-Cramer, Daniel J. Loes, Paul A. Caruso, David A. Williams, Kim Mouridsen, Kyrre E. Emblem, Florian S. Eichler & Patricia L. Musolino
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Summary:Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.
Item Description:Gesehen am 23.06.2023
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-023-37262-w

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