Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy.
Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy.
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DOI：
10.1038/s41467-023-37262-w
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发表时间：
2023-04-05
影响因子：
16.6
通讯作者：
Musolino, Patricia L.
中科院分区：
文献类型：
--
作者：
Lauer, Arne;Speroni, Samantha L.;Choi, Myoung;Da, Xiao;Duncan, Christine;McCarthy, Siobhan;Krishnan, Vijai;Lusk, Cole A.;Rohde, David;Hansen, Mikkel Bo;Kalpathy-Cramer, Jayashree;Loes, Daniel J.;Caruso, Paul A.;Williams, David A.;Mouridsen, Kim;Emblem, Kyrre E.;Eichler, Florian S.;Musolino, Patricia L.
血脑屏障破坏标志着脑性肾上腺脑白质营养不良 (CALD) 的发生，这是一种由 ABCD1 基因功能丧失引起的毁灭性脑脱髓鞘疾病。其潜在机制尚不清楚，但有证据表明微血管功能障碍参与其中。我们分析了用含有 ABCD1 cDNA 的 Lenti-D 慢病毒载体转导的自体造血干细胞治疗的 CALD 男孩的脑灌注成像，作为单组开放标签 2-3 期安全性和有效性研究 (NCT01896102) 的一部分，以及接受同种异体造血干细胞移植治疗的患者的脑灌注成像。我们发现白质通透性和微血管血流广泛且持续正常化。我们证明 ABCD1 功能性骨髓来源细胞可以植入脑血管和血管周围空间。基因剂量与病变生长之间的负相关表明，纠正的细胞长期有助于大脑微血管功能的重塑。需要进一步研究来探索这些影响的持续时间。脑性肾上腺脑白质营养不良 (CALD) 是一种由 ABCD1 基因功能丧失引起的脱髓鞘疾病。在这里，作者研究了接受自体造血干细胞基因治疗的 CALD 男孩的白质结构和微血管变化。
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. Cerebral adrenoleukodystrophy (CALD) is a demyelinating disease caused by loss of ABCD1 gene function. Here the authors investigate white matter structural and microvascular changes in boys with CALD that received gene therapy with autologous hematopoietic stem-cells.
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DOI：
10.1073/pnas.1205858109
发表时间：
2012-09-11
影响因子：
11.1
作者：
Capotondo, Alessia;Milazzo, Rita;Biffi, Alessandra
通讯作者：
Biffi, Alessandra
DOI：
10.1056/nejmoa1700554
发表时间：
2017-10-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eichler F;Duncan C;Musolino PL;Orchard PJ;De Oliveira S;Thrasher AJ;Armant M;Dansereau C;Lund TC;Miller WP;Raymond GV;Sankar R;Shah AJ;Sevin C;Gaspar HB;Gissen P;Amartino H;Bratkovic D;Smith NJC;Paker AM;Shamir E;O'Meara T;Davidson D;Aubourg P;Williams DA
通讯作者：
Williams DA
影响因子：
3.9
作者：
Kemp, S;Pujol, A;Hugo, HW
通讯作者：
Hugo, HW
DOI：
10.1038/jcbfm.2011.153
发表时间：
2012-02
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Jespersen SN;Østergaard L
通讯作者：
Østergaard L
影响因子：
9.9
作者：
Chen, Y. W.;Gurol, M. E.;Smith, E. E.
通讯作者：
Smith, E. E.