Safety and Biodistribution of a Novel Enzyme-Antibody Fusion in a Canine Model

Lafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no treatment or cure. Over the last 15 years, we and others have defined the molecular underpinnings of LD that position the field to cure this horrific disease. A hallmark of LD is cytosolic aberrant glycogen-like inclusions known as Lafora bodies (LBs) that accumulate in cells of most tissues, including the brain. Like patients, LD mouse models present with LBs and neurodegeneration. Reduced glycogen synthesis via genetic methods eliminates LB formation and rescues the neurological phenotype in LD mouse models. Thus, a current focus in the field is to decrease LBs with the goal of treating LD. Valerion/Enable Therapeutics has engineered a cell delivery platform utilizing antibody fragments allowing their antibody-enzyme fusions (AEFs) to deliver a protein into a myriad of cells. We recently identified therapeutic strategies to clear LBs involving the use of a novel targeting functionality fused to an active LB-degrading amylases, VAL-1221. We have completed in vitro proof of concept experiments and found that VAL-1221 degrade LBs. Further, in situ experiments demonstrate that it penetrates cells and has cellular activity. Our original plan for moving forward was to assess safety and biodistribution studies in a non-human primate model. However, for a variety of reasons, there is currently a world-wide shortage of research monkeys. Thus as an alternative we propose a canine model. In these studies we will perform a 30-day safety ICV study of VAL-1221R in a canine model. Collaborating with the Gerhardt laboratory, 4 male and 4 female dogs will be randomized to receive continuous ICV delivery of vehicle or VAL-1221R. The second Aim will determine the brain regional distribution and tissue penetrance of VAL- 1221R following ICV administration. 30 days after initiation of VAL-1221R treatment, dogs will be euthanized and the brains will be removed, dissected mid-sagittally and one hemisphere will be fixed for immunohistochemical studies, and the second frozen in liquid nitrogen for biochemical and metabolomic analysis. Additionally, CSF will be collected upon necropsy to test for VAL-1221R levels.