Treatment of Lafora Disease with an Antibody-Enzyme Fusion.

Of all the intractable epilepsies, Lafora disease (LD) is among the most severe. LD is an autosomal recessive, invariably fatal epilepsy that affects both sexes equally (1-3). Disease onset occurs in adolescence, affecting apparently healthy teenagers, with headaches and insidious decline in cognitive function. LD patients progress by exhibiting increased myoclonic seizures, staring spells, and generalized convulsions that all escalate over time. LD patients also develop highly frightening epileptic and non-epileptic visual hallucinations. Initial response to antiepileptic drugs is lost within three years and a constant myoclonus with atypical absence begins. The young person develops dementia, seizes with increased frequency, becomes bedridden, and death comes after a protracted decade of unceasing myoclonus in the form of status epilepticus or aspiration pneumonitis (4,5). LD is caused by mutations in either the Epilepsy, Progressive Myoclonus 2A (EPM2A) gene that encodes laforin or EPM2B that encodes malin (6-8). We have defined the biochemical activity of both proteins as critical regulators of glycogen metabolism (9-15). A hallmark of LD is periodic acid-Schiff (PAS) positive, aberrant, glycogen-like inclusions found in cells from nearly all tissues in the patients and in LD mouse models. Accumulation of these inclusions called Lafora bodies (LBs), is the primary neurological effector of LD in EPM2A and EPM2B patients (16-18). Multiple labs have demonstrated that the LB inclusions are the etiological agent of LD and recapitulated in mouse models of the disease (19-21). LD patients and animal models suffer a progressive accumulation of total glucan content. Notably, the LD models replicate LBs, myoclonus, reduced threshold for convulsions and cognitive impairment. These data validate LBs as the target for development of a treatment/cure of LD and has motivated discovery of a novel modality to degrade and clear LBs. In collaboration with Valerion Therapuetics, we are developing therapeutic strategies treat LD and other glycogen storage diseases such as Pompe’s disease (Glycogen storage disease type II [GSD-II]). VAL-1221 is a novel fusion protein that combines Valerion’s antibody-mediated delivery technology with recombinant human acid alpha-glucosidase (rhGAA [the enzyme missing in Pompe disease patients]). This approach uniquely targets both lysosomal and cytoplamic glycogen through enhanced intracellular delivery to affected tissues. By leveraging two uptake mechanisms, VAL-1221 has the potential to improve glycogen clearance and significantly improve patient outcomes. VAL-1221 is currently in a Phase 1/2 trial to evaluate the safety, pharmacokinetics, pharmacodynamics and immunogenicity of VAL-1221 in up to 12 patients with late-onset Pompe disease. We hypothesize that VAL-1221 will also be a highly efficacious drug-antibody conjugate for treatment of Lafora disease. However, the chemical make-up (ie. citrate buffer) of the current systemic (IV) formulation of VAL-1221 is not suitable for intracerebroventricular (ICV) administration and thus needs to be completely reformulated. In the R61 phase of the grant we will identify a stable liquid formulation of VAL-1221 that is safe for CNS administration and stable for delivery ICV infusion. The goal for the R33 phase of the proposal will be to study preclinical stability safety and efficacy of VAL-1221 to facilitate translation of this therapy into the clinic.