Antibody-enzyme fusions degrade pathogenic glycogen in Lafora disease and demonstrate a novel cell-penetrating platform for treating neurological disorders
M. Kathryn Brewer1, Annette Uittenbogaard1, Grant Austin1, John McCarthy1, Anna DePaoli-Roach2, Peter J. Roach2, Brad Hodges3, James R. Pauly3, Tracy McKnight3, Dustin D. Armstrong3*, Matthew S. Gentry1 1University of Kentucky, 2Indiana University, 3Valerion Therapeutics *email@example.com Lafora Disease (LD) is a neurodegenerative disorder typically fatal within 10 years of onset and characterized by the transformation of glycogen into malformed, aggregated inclusions called Lafora bodies (LBs). Insoluble LBs overtake the cytoplasm of neurons and generate a severe form of epilepsy. Using a proprietary antibody-delivery platform, Valerion Therapeutics has generated an alpha-glucosidase enzyme fusion (Fab-GAA) capable of uniquely penetrating cells and degrading accumulated glycogen. Currently, Fab-GAA is being clinically tested as a potential therapy for Pompe disease. In addition, Valerion has generated a novel amylase fusion (Fab-AMY) optimized to degrade glycogen at neutral pH. To determine whether either fusion could have efficacy in LD, both fusions were tested and demonstrated to have activity on different forms of glycogen and LBs. Despite generating unique breakdown products with regard to glucose, maltose, or other dextrin polymers, both fusions also demonstrated efficacy in vivo when administered by intramuscular (IM) injections or continuous intracerebroventricular (ICV) infusion. For example, Laforin KO mice receiving four weeks of Fab-AMY by ICV infusion had a 46% reduction in LBs in the brain, returning whole brain glycogen content to near normative levels in just one month (p < 0.05). Importantly, localization of Fab-AMY in treated brain sections revealed significant and widespread neuronal accumulation. These results show a clear promise for pursuing an antibody-enzyme treatment for Lafora disease. With activity against typically resilient LBs, there is a strong likelihood these fusions will also be active in other glycogen-driven diseases. Furthermore, the efficient distribution, uptake, and activity mediated by this platform highlight its potentially broad application to treat neuromuscular diseases; especially those disorders requiring enzymatic clearance of toxic oligomers or aggregated intracellular deposits.