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Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction.

ABSTRACT: OBJECTIVE:In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients. METHODS:Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age-matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t-test, linear regression or the nonparametric Mann-Whitney U-test was performed to evaluate differences between the transplanted, nontransplanted, and control group. RESULTS:In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti-inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross-correction to resident astrocytes and oligodendrocytes. INTERPRETATION:In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross-correction of oligo- and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.

SUBMITTER: Wolf NI

PROVIDER: S-EPMC7034505 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction.

Wolf Nicole I NI Breur Marjolein M Plug Bonnie B Beerepoot Shanice S Westerveld Aimee S R ASR van Rappard Diane F DF de Vries Sharon I SI Kole Maarten H P MHP Vanderver Adeline A van der Knaap Marjo S MS Lindemans Caroline A CA van Hasselt Peter M PM Boelens Jaap J JJ Matzner Ulrich U Gieselmann Volkmar V Bugiani Marianna M

Annals of clinical and translational neurology 20200122 2

<h4>Objective</h4>In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients.<h4>Methods</h4>Autopsy brain tissue was obtained from ...[more]

PMID: 31967741

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Project description:Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood-brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.

Project description:ObjectiveWe aimed to gain more insight into the pathomechanisms of metachromatic leukodystrophy (MLD), by comparing magnitude and direction of diffusion between patients and controls at diagnosis and during follow-up.MethodsFour late-infantile, 16 juvenile and 8 adult onset MLD patients [of which 13 considered eligible for hematopoietic cell transplantation (HCT)] and 47 controls were examined using diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were quantified and compared between groups using tract-based spatial statistics (TBSS). Diffusion measures were determined for normal-appearing white matter (NAWM), corpus callosum, thalamus (all based on subject-wise segmentation), and pyramidal tracts, determined with probabilistic tractography. Measures were compared between HCT-eligible patients, non-eligible patients and controls using general linear model and nonparametric permutation analyses (randomise) for TBSS data, considering family-wise error corrected p < 0.05 significant.ResultsThroughout white matter (WM), FA was decreased and MD and RD increased in both patient groups compared to controls, while AD was decreased in NAWM and corpus callosum. In the thalamus, no differences in FA were observed, but all diffusivities were increased in both patient groups. Differences were most pronounced between controls and patients non-eligible for HCT. Longitudinally (median follow-up 3.9 years), diffusion measures remained relatively stable for HCT-treated patients, but were progressively abnormal for non-eligible patients.InterpretationThe observed diffusion measures confirm that brain microstructure is changed in MLD, reflecting different pathological processes including loss of myelin and sulfatide accumulation. The observation of both increased and decreased AD probably reflects a balance between myelin and axonal loss vs. intracellular sulfatide storage in macrophages, depending on region and disease stage.

Dataset Information

Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction.

Publications

Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction.

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