Impaired plasticity of macrophages in X-linked adrenoleukodystrophy

Weinhofer, Isabelle; Zierfuss, Bettina; Hametner, Simon; Wagner, Magdalena; Popitsch, Niko; Machacek, Christian; Bartolini, Barbara; Zlabinger, Gerhard J.; Ohradanova‐Repic, Anna; Stockinger, Hannes; Köhler, Wolfgang; Höftberger, Romana; Regelsberger, Günther; Forss‐Petter, Sonja; Lassmann, Hans; Berger, Johannes

doi:10.1093/brain/awy127

Cited by 53 publications

(91 citation statements)

References 36 publications

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“…ALD patients have normal capacity for macrophage differentiation and phagocytosis; however, they are pro-inflammatory skewed in both CALD and AMN (Aubourg, 2015;Musolino et al, 2015;Musolino, Rapalino, Caruso, Caviness, & Eichler, 2012). ABCD1 deficiency leads to incomplete establishment of anti-inflammatory responses of macrophages possibly contributing to the rapidly progressive demyelination in CALD (Weinhofer et al, 2018).…”

Section: Oxidized Cholesterol Species May Contribute To Inflammationmentioning

confidence: 99%

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

117

113

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Adrenoleukodystrophy (ALD) is a rare X‐linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell‐ and tissue‐specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long‐chain fatty acid (VLCFA) chain length‐dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety‐specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.

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Section: Oxidized Cholesterol Species May Contribute To Inflammationmentioning

confidence: 99%

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

117

113

View full text Add to dashboard Cite

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“…1,2 Most affected tissues are white matter within the brain, spinal cord and adrenal cortex. 3,4 Microglial activation and apoptosis, 5 impairment of microglial anti-inflammatory function 6 as well as dysregulation of oxidative phosphorylation and mitochondrial function in neuroaxons 7 seem to be critical consequences of VLCFA accumulation in the brain.…”

mentioning

confidence: 99%

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Waldhüter

Köhler

Hemmati

et al. 2019

J of Inher Metab Disea

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The adult cerebral form of X‐linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic hematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), 8 with stable cognition and 7 of them with stable motor function (estimated event‐free survival 36 ± 17%). Death after transplantation occurred within the first year after HSCT and was caused either primarily by infection (N = 3) or due to disease progression triggered by infection (N = 1). Patients with minor myelopathic symptoms (N = 4) or with no or mild cerebral symptoms pre‐transplant (N = 7) had an excellent outcome. In contrast, no patient with major neurological symptoms associated with an extensive involvement of pyramidal tract fibres in the internal capsule (N = 5) survived without cognitive deterioration. Notably, early leukocyte recovery was associated with dismal outcome for yet unknown reasons. All 10 tested survivors showed a reduction of plasma hexacosanoic acid (C26:0) in the absence of Lorenzo's oil. Over time, the event‐free survival could be improved from 2 out of 8 patients (25%) before 2013 to 5 out of 7 patients (71%) thereafter. Therefore, allogeneic HSCT appears to be a suitable treatment option for carefully selected ACALD patients when transplanted from matched donors after myeloablative, busulfan‐based conditioning.

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“…It is possible that other factors, such as epigenetic or environmental factors, affect disease manifestation [19]. Blood brain barrier fragility, metabolic derangement, and a malfunctioning immune system are also potential secondary factors [20][21][22]. In spite of this ambiguity, all ALD patients possess the ABCD1 mutation.…”

Section: Discussionmentioning

confidence: 99%

Successful Correction of ALD Patient-derived iPSCs Using CRISPR/Cas9

Jung

Quan

Chang

et al. 2020

Preprint

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X-linked adrenoleukodystrophy (ALD) caused by the ABCD1 mutation, is the most common inherited peroxisomal disease. It is characterized by three phenotypes: inflammatory cerebral demyelination, progressive myelopathy, and adrenal insufficiency, but there is no genotype-phenotype correlation. Hematopoietic stem cell transplantation can only be used in a few patients in the early phase of cerebral inflammation; therefore, most affected patients have no curative option. Previously, we reported the generation of an ALD patient-derived iPSC model and its differentiation to oligodendrocytes. In this study, we have performed the first genome editing of ALD patient-derived iPSCs using homology-directed repair (HDR).The mutation site, c.1534G>A [GenBank: NM_000033.4], was corrected by introducing ssODN and the CRISPR/Cas9 system. The cell line exhibited normal ALD protein expression following genome editing. We differentiated the intermediate oligodendrocytes from mutation-corrected iPSCs and the metabolic derangement of ALD tended to correct but was not statistically significant. Mutation-corrected iPSCs from ALD patient can be used in research into the pathophysiology of and therapeutics for ALD.

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Impaired plasticity of macrophages in X-linked adrenoleukodystrophy

Cited by 53 publications

References 36 publications

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Successful Correction of ALD Patient-derived iPSCs Using CRISPR/Cas9

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