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

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 and Patricia L. Musolino ()
Additional contact information
Arne Lauer: Massachusetts General Hospital
Samantha L. Speroni: Massachusetts General Hospital
Myoung Choi: Massachusetts General Hospital
Xiao Da: Brigham and Women’s Hospital
Christine Duncan: Dana–Farber and Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School
Siobhan McCarthy: Massachusetts General Hospital
Vijai Krishnan: Massachusetts General Hospital
Cole A. Lusk: Massachusetts General Hospital
David Rohde: Massachusetts General Hospital
Mikkel Bo Hansen: Aarhus University
Jayashree Kalpathy-Cramer: Athinoula A. Martinos Centre for Biomedical Imaging
Daniel J. Loes: Suburban Radiologic Consultants, Ltd
Paul A. Caruso: Massachusetts General Hospital
David A. Williams: Dana–Farber and Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School
Kim Mouridsen: Aarhus University
Kyrre E. Emblem: Oslo University Hospital
Florian S. Eichler: Massachusetts General Hospital
Patricia L. Musolino: Massachusetts General Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37262-w

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