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 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. In collaboration with Valerion, we recently identified therapeutic strategies to clear LBs. This involves use of a novel targeting functionality fused to active LB-degrading amylases, called VAL-0417 and VAL-1221. We have completed in vitro proof of concept experiments and found that VAL-0417 and VAL-1221 degrade LBs. Further, in situ experiments demonstrate that they penetrate cells and they are active in cells. Strikingly, we see that intracerebroventricular (ICV) injection of VAL-0417 and VAL-1221 efficiently degrade LBs in LD mouse models, lowering total glucan levels of LD mouse brains to near WT levels. Pompe disease is a classical glycogen storage disease caused by lack of the lysosomal enzyme acid ?- glucosidase (GAA) that normally degrades glycogen. Valerion has completed pre-clinical studies with VAL- 1221 and initiated a Phase 1/2 clinical trial. This trail involves IV administration of VAL-1221. However, the current VAL-1221 formulation is not suitable for human ICV injections. Therefore, this proposal will:
Specific Aims for the R61 phase of the grant (1 year) Specific Aim 1 ? Reformulate VAL-1221 for ICV delivery. A series of go/no-go studies will be performed to optimize the activity and stability of VAL-1221. We will also determine the brain biodistribution, pharmacokinetic (PK), and pharmacodynamic (PD) parameters of ICV VAL-1221.
Specific Aims for the R33 phase of the grant (2 years) Specific Aim 2 ? Establish the optimal in vivo dosing strategy for ICV VAL-1221. We will perform a dose escalation study to determine the maximum tolerated dose of ICV VAL-1221, along with studies that will assess the duration and frequency of ICV VAL-1221 administration that most efficaciously improves glucan clearance from the brains of Laforin knockout mice that have extensive pathological load, i.e. LBs. We are poised to perform the preclinical research required to translate this therapy into the clinic. Additionally, VAL-1221 is a novel approach with potential beyond LD.

Public Health Relevance

Lafora disease (LD) is a catastrophic epilepsy that strikes healthy teenagers and leads to constant ever- worsening seizures until it results in death after 10 years. The collaboration in this proposal brings together scientists at the University of Kentucky and Valerion Therapeutics that have identified a cure for LD in mouse models. Our vision is that one day a physician having diagnosed a child with this horrendous epilepsy would have the medicines and technologies to stop the disease in its tracks so that the child is able to resume development and life a healthy and normal life. !

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Roof, Rebecca
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University of Kentucky
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