Brain cell type-specific endocytosis of arylsulfatase A identifies limitations of enzyme-based therapies for metachromatic leukodystrophy

Kaminski, Debora; Yaghootfam, Claudia; Matthes, Frank; Reßing, Annika; Gieselmann, Volkmar; Matzner, Ulrich

doi:10.1093/hmg/ddaa277

Cited by 14 publications

(11 citation statements)

References 45 publications

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“…This might reflect progressive peripheral neuropathy after HSCT, 44 or, more likely, the fact that enzymatic cross-correction of neurons and neuroglia after HSCT is limited if present at all, leading to a suboptimal treatment effect. 8 , 45 , 46 Nevertheless, in accordance with previous findings of better treatment outcomes, 9 , 11 , 47–49 patients who underwent transplantation at a presymptomatic stage exhibited lower bNfL levels over time than patients at a symptomatic stage. This finding again underlines the importance of early treatment in MLD.…”

Section: Discussionsupporting

confidence: 87%

Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy

Beerepoot

Heijst

Roos

et al. 2021

Brain

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Metachromatic leukodystrophy is a lethal metabolic leukodystrophy, with emerging treatments for early disease stages. Biomarkers to measure disease activity are required for clinical assessment and treatment follow-up. This retrospective study compared neurofilament light chain and glial fibrillary acidic protein levels in CSF (n = 11) and blood (n = 92) samples of 40 patients with metachromatic leukodystrophy (aged 0–42 years) with 38 neurologically healthy children (aged 0–17 years) and 38 healthy adults (aged 18–45 years), and analyzed the associations between these levels with clinical phenotype and disease evolution in untreated and transplanted patients. Metachromatic leukodystrophy subtype was determined based on the (expected) age of symptom onset. Disease activity was assessed by measuring gross motor function deterioration and brain MRI. Longitudinal analyses with measurements up to 23 years after diagnosis were performed using linear mixed models. CSF and blood neurofilament light chain and glial fibrillary acidic protein levels in pediatric controls were negatively associated with age (all P < 0.001). Blood neurofilament light chain level at diagnosis (median, interquartile range; picogram per milliliter) was significantly increased in both pre-symptomatic (14.7, 10.6–56.7) and symptomatic patients (136, 40.8–445) compared to controls (5.6, 4.5–7.1), and highest amongst patients with late-infantile (456, 201–854) or early-juvenile MLD (291.0, 104–445) and those ineligible for treatment based on best practice (291, 57.4–472). Glial fibrillary acidic protein level (median, interquartile range; picogram per milliliter) was only increased in symptomatic patients (591, 224–1150) compared to controls (119, 78.2–338) and not significantly associated with treatment eligibility (P = 0.093). Higher blood neurofilament light chain and glial fibrillary acidic protein levels at diagnosis were associated with rapid disease progression in late-infantile (P = 0.006 and P = 0.051, respectively) and early-juvenile patients (P = 0.048 and P = 0.039, respectively). Finally, blood neurofilament light chain and glial fibrillary acidic protein levels decreased during follow-up in untreated and transplanted patients but remained elevated compared with controls. Only neurofilament light chain levels were associated with MRI deterioration (P < 0.001). This study indicates that both proteins may be considered as non-invasive biomarkers for clinical phenotype and disease stage at clinical assessment, and that neurofilament light chain might enable neurologists to make better informed treatment decisions. In addition, neurofilament light chain holds promise assessing treatment response. Importantly, both biomarkers require pediatric reference values, given that their levels first decrease before increasing with advancing age.

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Section: Discussionsupporting

confidence: 87%

Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy

Beerepoot

Heijst

Roos

et al. 2021

Brain

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“…However, when Galc-competent macrophages are present, the phenotype is attenuated ( 19 ). Related findings have been described for ASA (arylsulfatase A), the enzyme defective in the sister disease metachromatic leukodystrophy ( 70 ).…”

Section: Discussionsupporting

confidence: 64%

Expression of Ripk1 and DAM genes correlates with severity and progression of Krabbe disease

Cachón‐González

Cox

2021

Human Molecular Genetics

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Krabbe disease, an inherited leukodystrophy, is a sphingolipidosis caused by deficiency of β-galactocerebrosidase: it is characterized by myelin loss, and pathological activation of macrophage/microglia and astrocytes. To define driving pathogenic factors, we explored the expression repertoire of candidate neuroinflammatory genes: upregulation of receptor interacting protein kinase 1 (Ripk1) and disease-associated microglia (DAM) genes, including Cst7 and Ch25h, correlated with severity of Krabbe disease genetically modelled in the twitcher mouse. Upregulation of Ripk1 in Iba1/Mac2-positive microglia/macrophage associated with the pathognomic hypertrophic/globoid phenotype of this disease. Widespread accumulation of ubiquitinin1 in white and grey matter co-localised with p62. In Sandhoff disease, another sphingolipid disorder, neuroinflammation, accumulation of p62 and increased Ripk1 expression was observed. The upregulated DAM genes and macrophage/microglia expression of Ripk1 in the authentic model of Krabbe disease strongly resemble those reported in Alzheimer disease associating with disturbed autophagosomal/lysosomal homeostasis. Activation of this shared molecular repertoire, suggests the potential for therapeutic interdiction at a common activation step, irrespective of proximal causation. To clarify the role of Ripk1 in the pathogenesis of Krabbe disease, we first explored the contribution of its kinase function, by intercrossing twitcher and the K45A kinase-dead Ripk1 mouse and breeding to homozygosity. Genetic ablation of Ripk1 kinase activity neither altered the neuropathological features nor the survival of twitcher mice. We conclude that Ripk1 kinase-dependent inflammatory and degenerative capabilities play no instrumental role in Krabbe disease; however, putative kinase-independent functions of Ripk1 remain formally to be explored in its molecular pathogenesis.

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“… 69 Finally, macrophages appear to be the most readily cross-corrected cell type via both M6PR and M6PR-independent pathways. 70 This suggests that macrophages, which migrate to the CNS and PNS, could be cross corrected locally in a context of robust neuronal or astrocytic enzyme expression after ICM gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of a Krabbe Disease Gene Therapy

et al. 2022

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Krabbe disease is a lysosomal storage disease caused by mutations in the gene that encodes galactosylceramidase, in which galactosylsphingosine (psychosine) accumulation drives demyelination in the central and peripheral nervous systems, ultimately progressing to death in early childhood. Gene therapy, alone or in combination with transplant, has been developed for almost two decades in mouse models, with increasing therapeutic benefit paralleling the improvement of next-generation adeno-associated virus (AAV) vectors. This effort has recently shown remarkable efficacy in the canine model of the disease by two different groups that used either systemic or cerebrospinal fluid (CSF) administration of AAVrh10 or AAV9. Building on our experience developing CSF-delivered, AAV-based drug products for a variety of neurodegenerative disorders, we conducted efficacy, pharmacology, and safety studies of AAVhu68 delivered to the CSF in two relevant natural Krabbe animal models, and in nonhuman primates. In newborn Twitcher mice, the highest dose (1 × 10 11 genome copies [GC]) of AAVhu68.hGALC injected into the lateral ventricle led to a median survival of 130 days compared to 40.5 days in vehicle-treated mice. When this dose was administered intravenously, the median survival was 49 days. A single intracisterna magna injection of AAVhu68.cGALC at 3 × 10 13 GC into presymptomatic Krabbe dogs increased survival for up to 85 weeks compared to 12 weeks in controls. It prevented psychosine accumulation in the CSF, preserved peripheral nerve myelination, ambulation, and decreased brain neuroinflammation and demyelination, although some regions remained abnormal. In a Good Laboratory Practice-compliant toxicology study, we administered the clinical candidate into the cisterna magna of 18 juvenile rhesus macaques at 3 doses that displayed efficacy in mice. We observed no dose-limiting toxicity and sporadic minimal degeneration of dorsal root ganglia (DRG) neurons. Our studies demonstrate the efficacy, scalability, and safety of a single cisterna magna AAVhu68 administration to treat Krabbe disease. ID: NCT04771416.

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Brain cell type-specific endocytosis of arylsulfatase A identifies limitations of enzyme-based therapies for metachromatic leukodystrophy

Cited by 14 publications

References 45 publications

Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy

Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy

Expression of Ripk1 and DAM genes correlates with severity and progression of Krabbe disease

Efficacy and Safety of a Krabbe Disease Gene Therapy

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