Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion
| Autor: | Grant L. Austin, John J. McCarthy, Annette Uittenbogaard, Jill Zeller, Tracy R. McKnight, Anna A. DePaoli-Roach, Dustin Armstrong, Dyann M. Segvich, M. Kathryn Brewer, James R. Pauly, Bradley L. Hodges, Matthew S. Gentry, Peter J. Roach |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
biology Glycogen Neurodegeneration medicine.disease Lafora disease 3. Good health Ubiquitin ligase 03 medical and health sciences Epilepsy chemistry.chemical_compound 0302 clinical medicine chemistry medicine biology.protein Cancer research Antibody Glycogen synthase Laforin 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/679407 |
| Popis: | 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 theEPM2AorEPM2Bgenes 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 LBsin vitro, shows robust cellular uptake, and significantly reduces the LB loadin vivoinEpm2a-/- 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.One Sentence SummaryAn antibody-enzyme fusion delivering an amylase degrades the toxic polyglucosan bodies that cause Lafora disease, a fatal childhood epilepsy. |
| Databáze: | OpenAIRE |
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