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.

Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease

“…We theorize that the lack of rescue may be explained by GALC levels that are too low, expressed in the wrong cell type, or present at the wrong time period. Furthermore, cross-correction of GALC 27 (and other lysosomal hydrolases 28 ) may not be very efficient in vivo, and therefore, the function of GALC may be restricted to the subset of cells that directly express it. A similar correlate exists regarding refractory moribund pathology observed in HSCT-treated twitcher and KD patients despite the detection of substantial GALC activity 29 – 32 .…”

Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease

“…Microglia are known to be involved in a number of key neurodevelopmental processes, such as the clearance of apoptotic cell bodies and pruning of synapses (Marín‐Teva et al, 2004; Paolicelli et al, 2011), and defects in this lineage have been linked to a wide range of neurological diseases, including LSDs. Recent studies of other leukodystrophies, including lysosomal metachromatic leukodystrophy and Krabbe disease, as well as a recently discovered leukodystrophy involving the absence of microglia, have suggested that microglial abnormalities may contribute to their pathogenesis (Oosterhof et al , 2019; Weinstock et al , 2020; Wolf et al , 2020). The early finding of microglial abnormalities in our zebrafish model supports this hypothesis, although further studies are needed to determine the contribution of this cell type, and others, to the pathology of vps16 disruption.…”

Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy

“…Over the past 20 years, hematopoietic stem cell transplantation (HSCT) has been the only clinically available therapeutic option for juvenile MLD [ 5 ]. The rationale is that monocytic bone marrow cells can cross the blood–brain barrier, migrate into the brain, differentiate into microglia cells and produce the missing enzyme, thereby enabling re-myelination [ 6 , 7 ]. It takes up to 12–24 months until disease stabilization occurs because of the slow replacement of resident tissue [ 5 , 8 – 10 ], which in turn makes HSCT ineffective in children with the rapidly progressive late-infantile form and in juvenile patients with advanced symptoms [ 11 ].…”