Astrocytes: new players in progressive myoclonus epilepsy of Lafora type

Rubio-Villena, Carla; Viana, Rosa; Bonet, José; García-Gimeno, Maria Adelaida; Casado, Marta; Heredia, Miguel López de; Sanz, Pascual

doi:10.1093/hmg/ddy044

Cited by 52 publications

(52 citation statements)

References 45 publications

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“…6D). This is the first time polysaccharide distribution across different brain regions has been quantitated in Epm2a-/-mice, and is consistent with the high levels of LBs observed in histological sections from brainstem and cerebellum (3,10,11). Treatment with VAL-0417 reduced the polysaccharide load in all sections, with statistical significance in the two most caudal sections that contain the highest glucan load ( Fig 6D).…”

Section: In Vivo Uptake Of Val-0417 and Lb Reduction In Epm2a-/-micesupporting

confidence: 83%

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Brewer

Uittenbogaard

Austin

et al. 2019

Preprint

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One Sentence Summary: An antibody-enzyme fusion delivering an amylase degrades the toxic polyglucosan bodies that cause Lafora disease, a fatal childhood epilepsy.Abstract: Lafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no effective therapy or cure. LD is caused by recessive mutations in the EPM2A or EPM2B genes that encode the glycogen phosphatase laforin and an E3 ubiquitin ligase malin, respectively. A hallmark of LD is the intracellular accumulation of abnormal and insoluble α linked polysaccharide deposits known as Lafora bodies (LBs) in several tissues, including most regions of the brain. In mouse models of LD, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Since multiple groups have confirmed that neurodegeneration and epilepsy result from LB accumulation, a major focus in the field has shifted toward the development of therapies that reduce glycogen synthesis or target LBs for degradation with the goal of treating LD. Herein, we identify the optimal enzymes for degrading LBs, and we develop a novel therapeutic agent by fusing human pancreatic α -amylase to a cellpenetrating antibody fragment. This antibody-enzyme fusion (VAL-0417) degrades LBs in vitro, shows robust cellular uptake, and significantly reduces the LB load in vivo in Epm2a-/-mice. VAL-0417 is a promising therapeutic for the treatment of LD and a putative precision therapy for an intractable epilepsy. Antibody-enzyme fusions represent a new class of antibody-based drugs that could be utilized to treat glycogen storage disorders and other diseases. The progressive myoclonic epilepsies (PMEs) are a group of inherited disorders characterized by recurrent seizures, myoclonus, and progressive neurological decline. There are currently no treatments for PMEs, and anti-epilepsy drugs are palliative at best (1). Lafora disease (LD; epilepsy, progressive myoclonus type 2, EPM2) is a severe form of PME that typically manifests with tonic-clonic seizures and myoclonic jerks in the early teen years followed by rapid neurological deterioration, increasingly severe and frequent epileptic episodes, dementia and death within ten years of onset (OMIM: 254780). LD is caused by mutations in the EPM2A or EPM2B genes that encode laforin, a glycogen phosphatase, and malin, an E3 ubiquitin ligase that ubiquitinates enzymes involved in glycogen metabolism (reviewed in (2)). LD is distinguishable from other PMEs by the presence of cytosolic polysaccharide inclusions known as Lafora bodies (LBs) most notably in the brain, where they are found in neuronal cell bodies and dendrites and astrocytic processes, and in other tissues such as muscle, heart, and liver (3-5). Among the PMEs LD is uniquely considered a non-classical glycogen storage disease (GSD) (6, 7). Independent studies from multiple groups demonstrate that Epm2a-/-and Epm2b-/-mice recapitulate disease symptoms with respect to LB formation, neurodegeneration, neurological impairments, and susceptibil...

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Section: In Vivo Uptake Of Val-0417 and Lb Reduction In Epm2a-/-micesupporting

confidence: 83%

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Brewer

Uittenbogaard

Austin

et al. 2019

Preprint

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“…Perhaps the presence of these inclusions inside the astrocyte triggers a stress reaction in the form of a release of pro-inflammatory mediators, chemokines and cytokines, which would initiate the inflammatory reaction. Microglia may also contribute in the same way, as we also observed microglial cells loaded with polyglucosan inclusions [ 75 ].…”

Section: Pathophysiological Consequences Of a Dysfunctional Laforimentioning

confidence: 74%

“…Another possibility is that the accumulation of LBs is the initial event that triggers inflammation. In line with this latter possibility, we have recently described that astrocytes are the main brain cellular type that accumulates polyglucosan inclusions in animal models of LD [ 75 ]. Perhaps the presence of these inclusions inside the astrocyte triggers a stress reaction in the form of a release of pro-inflammatory mediators, chemokines and cytokines, which would initiate the inflammatory reaction.…”

Section: Pathophysiological Consequences Of a Dysfunctional Laforimentioning

confidence: 85%

“…In this sense, we have recently described a defect in mitophagy, most likely due again to defects in autophagosome formation [ 65 ] ( Table 2 ). Autophagy impairment could affect negatively glycogen degradation, as one of the glycogenolytic pathways involves lysosomes, but we have recently observed in astrocytes from mouse models of LD that the main glycogen degradation involves cytosolic glycogen phosphorylase and not lysosomal α-glucosidase [ 75 ].…”

Section: Pathophysiological Consequences Of a Dysfunctional Laforimentioning

confidence: 99%

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Lafora Disease: A Ubiquitination-Related Pathology

García-Gimeno

Knecht

Sanz

2018

Cells

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Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named Lafora bodies (LBs). LD is caused by mutations in the EPM2A gene, encoding the dual phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Laforin and malin form a functional complex that is involved in the regulation of glycogen synthesis. Thus, in the absence of a functional complex glycogen accumulates in LBs. In addition, it has been suggested that the laforin-malin complex participates in alternative physiological pathways, such as intracellular protein degradation, oxidative stress, and the endoplasmic reticulum unfolded protein response. In this work we review the possible cellular functions of laforin and malin with a special focus on their role in the ubiquitination of specific substrates. We also discuss here the pathological consequences of defects in laforin or malin functions, as well as the therapeutic strategies that are being explored for LD.

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“…2–4 LBs form in cells from nearly all tissues but are most insidious in neurons and astrocytes where they cause neurodegeneration. 5,6 LD is the result of mutations in either Epilepsy , Progressive Myoclonus type 2A ( EPM2A ) or EPM2B , encoding the glycogen phosphatase laforin and the E3-ubiquitin ligase malin, respectively. 1,7–9…”

Section: Introductionmentioning

confidence: 99%

Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease

Austin

Simmons

Klier

et al. 2019

Preprint

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Lafora disease is a fatal juvenile epilepsy, characterized by the malignant accumulation of aberrant glucan inclusions called Lafora Bodies (LBs). Cerebral delivery of protein-based therapeutics for the clearance of Lafora Bodies remain a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and been proposed as a broadly applicable carrier to mediate cellular targeting and uptake. We report studies on cerebral delivery of VAL-0417, an antibody-enzyme fusion composed of the 3E10 hFab and human pancreatic α-amylase for the clearance of LBs in a mouse model of lafora disease. Herein, we report development of an enzyme-linked immunosorbant-based bioassay to detect VAL-0417 post treatment as a measure of delivery efficacy. We demonstrate the robust and sensitive detection of the fusion protein in multiple tissue types. Using our method, we measured biodistribution in different methods of delivery. We found intracerebroventricular administration provided the most robust delivery, while intrathecal administration only showed modest biodistribution. These data define critical steps in the translational pipeline of VAL-0417for the treatment of Lafora disease.

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Astrocytes: new players in progressive myoclonus epilepsy of Lafora type

Cited by 52 publications

References 45 publications

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

Lafora Disease: A Ubiquitination-Related Pathology

Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease

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