Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice

Damme, Markus; Jeugd, Anneke Van der; Vermaercke, Ben; Andersson, Claes; Fogh, Jørgen; Säftig, Paul; Blanz, Judith; D’Hooge, Rudi

doi:10.1016/j.nbd.2017.07.013

Cited by 9 publications

(6 citation statements)

References 64 publications

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“…Numerous studies have explored the binding and uptake of extreme glycoforms, such as high-Man- and high/low-M6P-containing lysosomal enzymes 6–9 , but systematic studies investigating the complex interplay between different glycan features have not been possible due to the lack of methods to produce such glycoforms. Studies with, for example, the lysosomal α‐mannosidase that contains multiple N-glycans with very low M6P content and exposure of Man when produced in WT CHO cells suggest that limited interaction with the MPRs and MR may be advantageous for wider biodistribution and crossing into the brain, possibly due to extended circulation time 48,57 . Similar findings were observed with postproduction modified enzymes with partially destroyed glycans 26 .…”

Section: Discussionmentioning

confidence: 99%

The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells

Tian

Wang

et al. 2019

Nat Commun

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Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of α-galactosidase A in a Fabry disease mouse model, and find that an α2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.

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Section: Discussionmentioning

confidence: 99%

The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells

Tian

Wang

et al. 2019

Nat Commun

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“…Enzyme replacement therapy (ERT) remains the most accepted treatment regimen for LSD although it is widely accepted that systemic ERT cannot effectively manage neurological indications due to inability of the recombinant enzyme to pass the blood-brain barrier. Interestingly, a study by Stroobants et al [127] reports that systemic administration of recombinant human α-mannosidase through tail vain injections for 7 months (starting at 2 and continuing until 9 months) in an immune-tolerant mouse model for α-mannosidosis improved spatial cognitive performance in the Morris water maze task. LTP induced by stimulation of SC to CA1 neurons in the hippocampus was also found to be increased with a concomitant reduction in primary substrate storage and neuroinflammation.…”

Section: Functional Synaptic Defectsmentioning

confidence: 99%

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Pará

Bose

Pshezhetsky

2020

JCM

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About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage affects biogenesis and function of neurons is still under investigation however recent research highlights a substantial role played by synaptic defects, such as alterations in synaptic spines, synaptic proteins, postsynaptic densities, and synaptic vesicles that might lead to functional impairments in synaptic transmission and neurodegeneration, finally culminating in massive neuronal death and manifestation of cognitive symptoms. Unveiling how the synaptic components are affected in neurological LSD will thus enable a better understanding of the complexity of disease progression as well as identify crucial targets of therapeutic relevance and optimal time windows for targeted intervention.

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“…Both compounds did not yet receive formal approval by the FDA for the treatment of alpha‐mannosidosis . There is a mouse model for alpha‐mannosidosis in which preclinical studies of IV—administered enzyme replacement therapy were conducted . Addressing the issue of the blood‐brain barrier, preclinical studies of gene therapy based on a single cisterna magna infusion of adeno‐associated virus type 1 expressing feline alpha‐mannosidase gene were conducted in cats .…”

Section: Introductionmentioning

confidence: 99%

Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

Zielonka

Garbade

Kölker

et al. 2019

J of Inher Metab Disea

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Alpha‐mannosidosis (OMIM 248500) is a rare lysosomal storage disorder caused by a deficiency of the enzyme alpha‐mannosidase. Recently, enzyme replacement therapy was approved in the European Union for the treatment of alpha‐mannosidosis, but evaluation regarding long‐term efficacy and safety is hard to assess due to missing quantitative natural history data, in particular survival. We performed a quantitative analysis of published cases (N = 111) with alpha‐mannosidosis. Main outcome measures were age of disease onset, diagnostic delay and survival (overall and by subgroup exploration). Residual alpha‐mannosidase activity and age of onset were explored as potential predictors of survival. STROBE criteria were respected. Median age of onset was 12 months. Median diagnostic delay was 6 years. At the age of 41 years 72.3% of patients were alive (N = 111). Residual alpha‐mannosidase activity (N = 34) predicted survival: Patients with a residual alpha‐mannosidase activity below or equal to 4.5% of normal in fibroblasts had a median survival of 3.5 years, whereas patients with alpha‐mannosidase activity above this threshold all survived during the observation period reported. Patients with age of onset above 7 years survived significantly longer than patients with age of onset below or equal to 7 years. Patient distribution was panethnic with hotspots in the United States and Germany. We defined age of onset, diagnostic delay, and survival characteristics in a global cohort of 111 patients with alpha‐mannosidosis by retrospective quantitative natural history modeling. These data expand the quantitative understanding of the clinical phenotype.

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Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice

Cited by 9 publications

References 64 publications

The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells

The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

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