Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a−/− mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a−/− 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.
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This work is supported by a sponsored project to M.S.G. from Valerion Therapeutics, NIH R01 NS070899 to M.S.G., P01 NS097197 to M.S.G., Epilepsy Foundation New Therapy Commercialization Grant to M.S.G., and F31 NS093892 to M.K.B. Funding for the University of Kentucky Alzheimer’s Disease Center (P30 AGO28383) and the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the UK Markey Cancer Center (P30 CA177558) also contributed to this work.
The supplemental information is included in the downloadable document.
Brewer, M. Kathryn; Uittenbogaard, Annette M.; Austin, Grant L.; Segvich, Dyann M.; DePaoli-Roach, Anna; Roach, Peter J.; McCarthy, John J.; Simmons, Zoe R.; Brandon, Jason A.; Zhou, Zhengqiu; Zeller, Jill; Young, Lyndsay E. A.; Sun, Ramon C.; Pauly, James R.; Aziz, Nadine M.; Hodges, Bradley L.; McKnight, Tracy R.; Armstrong, Dustin D.; and Gentry, Matthew S., "Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion" (2019). Molecular and Cellular Biochemistry Faculty Publications. 158.
Available for download on Saturday, July 25, 2020