The role of brain barriers in fluid movement in the CNS: is there a glymphaticsystem? Acta neuropathologica 135, 387C407

The role of brain barriers in fluid movement in the CNS: is there a glymphaticsystem? Acta neuropathologica 135, 387C407. a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic -amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs and dramatically reduces LB loads in mice. Using metabolomics and multivariate analysis we demonstrate that VAL-0417 treatment of mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy. Graphical Abstract eTOC blurb Lafora disease (LD) is a devastating childhood epilepsy caused by intracellular glycogen aggregates called Lafora bodies (LBs) in the brain and other tissues. Herein, Brewer et al. generated a first-in-class antibody-enzyme fusion, VAL-0417, that degrades LBs and pre-clinical models, showing promise as a LD drug. Introduction The progressive myoclonic epilepsies (PMEs) are a group of inherited disorders characterized by recurrent seizures, myoclonus, and progressive neurological decline. GSK9311 There are currently no treatments for PMEs, and anti-epilepsy drugs are palliative at best (Shahwan et al., 2005). 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 or genes that encode laforin, a glycogen phosphatase, and malin, an E3 ubiquitin ligase that ubiquitinates enzymes involved in glycogen metabolism (reviewed in (Gentry et al., 2018)). 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 dendrites, and GSK9311 astrocytic processes, and in other tissues such as muscle, heart, and liver. Among the PMEs, LD is uniquely considered a glycogen storage disease (GSD). Independent studies from multiple groups demonstrated that and and mice lacking glycogen synthase (mice were crossed with mice (Pederson et al., 2013). Furthermore, mice lacking just one allele in the brain have reduced glycogen and also show near complete rescue of these phenotypes (Duran et al., 2014). mice lacking Protein Targeting to Glycogen (PTG), a protein that promotes glycogen synthesis, also exhibit reduced LB accumulation, and neurodegeneration and myoclonic epilepsy are resolved in these animals (Turnbull et al., 2011; Turnbull et al., 2014). These results demonstrate that decreased or complete absence of the glycogen synthesis machinery ablates LB formation and neurodegeneration in LD mouse models. The reverse has also been observed: overexpression of a constitutively active form of glycogen synthase in otherwise wild type animals drives neurodegeneration in both flies and mice (Duran GSK9311 et al., 2012). The accumulating polysaccharide in transgenic animals overexpressing glycogen synthase is a polyglucosan (i.e. abnormal) rather than normal glycogen (Raben et al., 2001). Collectively, the aforementioned studies demonstrate that cerebral LB accumulation is pathogenic. These studies have both elucidated the molecular etiology of LD and have made LBs an obvious therapeutic target. Efforts to develop a targeted therapy (i.e. precision medicine) for LD are ongoing (Brewer and Gentry, 2018; Brewer et al., 2019). One form of precision medicine that has been utilized for treating GSDs is the introduction of exogenous replacement enzymes. Enzyme replacement therapy has proven effective for Pompe disease (OMIM: 232300), an inherited GSD (van der Ploeg et al., 2010). Pompe patients are deficient in the lysosomal Rabbit Polyclonal to MAP2K1 (phospho-Thr386) enzyme that degrades glycogen, acid a-glucosidase (GAA), and GSK9311 are currently treated with a recombinant human form of this protein known as rhGAA or alglucosidase alfa (Myozyme?, Lumizyme?, Genzyme) (Kishnani et al., 2007; van der Ploeg et al., 2010). The uptake of rhGAA is a receptor-mediated endocytic process that targets rhGAA to the lysosome. However, there is a significant portion of cytosolic glycogen in Pompe patients, and since rhGAA only targets lysosomal glycogen, those with large.

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