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; Patricia L. Musolino

doi:10.1038/s41467-023-37262-w

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, Patricia L. Musolino^*

^*Corresponding author for this work

Department of Clinical Medicine - Center of Functionally Integrative Neuroscience

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

12 Citations (Scopus)

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.

Original language	English
Article number	1900
Journal	Nature Communications
Volume	14
Issue	1
Number of pages	10
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-37262-w
Publication status	Published - Dec 2023

Access to Document

10.1038/s41467-023-37262-wLicence: CC BY

Library access?

Check availability with the Royal Danish Library

Cite this

Lauer, A., Speroni, S. L., Choi, M., Da, X., Duncan, C., McCarthy, S., Krishnan, V., Lusk, C. A., Rohde, D., Hansen, M. B., Kalpathy-Cramer, J., Loes, D. J., Caruso, P. A., Williams, D. A., Mouridsen, K., Emblem, K. E., Eichler, F. S., & Musolino, P. L. (2023). Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy. Nature Communications, 14(1), Article 1900. https://doi.org/10.1038/s41467-023-37262-w

@article{0095493423a346a5b9a1c499ab61bfb0,

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

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.",

author = "Arne Lauer and Speroni, \{Samantha L.\} and Myoung Choi and Xiao Da and Christine Duncan and Siobhan McCarthy and Vijai Krishnan and Lusk, \{Cole A.\} and David Rohde and Hansen, \{Mikkel Bo\} and Jayashree Kalpathy-Cramer and Loes, \{Daniel J.\} and Caruso, \{Paul A.\} and Williams, \{David A.\} and Kim Mouridsen and Emblem, \{Kyrre E.\} and Eichler, \{Florian S.\} and Musolino, \{Patricia L.\}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-37262-w",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Lauer, A, Speroni, SL, Choi, M, Da, X, Duncan, C, McCarthy, S, Krishnan, V, Lusk, CA, Rohde, D, Hansen, MB, Kalpathy-Cramer, J, Loes, DJ, Caruso, PA, Williams, DA, Mouridsen, K, Emblem, KE, Eichler, FS & Musolino, PL 2023, 'Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy', Nature Communications, vol. 14, no. 1, 1900. https://doi.org/10.1038/s41467-023-37262-w

Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy. / Lauer, Arne; Speroni, Samantha L.; Choi, Myoung et al.
In: Nature Communications, Vol. 14, No. 1, 1900, 12.2023.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy

AU - Lauer, Arne

AU - Speroni, Samantha L.

AU - Choi, Myoung

AU - Da, Xiao

AU - Duncan, Christine

AU - McCarthy, Siobhan

AU - Krishnan, Vijai

AU - Lusk, Cole A.

AU - Rohde, David

AU - Hansen, Mikkel Bo

AU - Kalpathy-Cramer, Jayashree

AU - Loes, Daniel J.

AU - Caruso, Paul A.

AU - Williams, David A.

AU - Mouridsen, Kim

AU - Emblem, Kyrre E.

AU - Eichler, Florian S.

AU - Musolino, Patricia L.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85151786331&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-37262-w

DO - 10.1038/s41467-023-37262-w

M3 - Journal article

C2 - 37019892

AN - SCOPUS:85151786331

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1900

ER -

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

Abstract

Access to Document

Library access?

Other files and links

Fingerprint

Cite this