Scope: KYNETIC-Novel enzyme therapeutics targeting Alzheimer’s disease

Fifty million people currently live with Alzheimer’s Disease (AD) worldwide and this figure is expected to rise to over 152 million by 2050 as the baby-boomer generation ages. The current treatment market, worth over $5 billion, consists of only five FDA approved drugs for AD and each only temporarily improves cognition without modifying the underlying disease pathology. AD research has focused on primarily two proteins as therapeutic targets, beta-amyloid and tau, and R&D efforts have not yielded a new therapy since 2003. Defective glucose metabolism is a clinical hallmark in AD patients. We recently discovered that AD patients develop large glucose aggregates, known as polyglucosan bodies (PGBs), and PGBs are known to drive cognitive impairments and neurodegeneration in other neurological disorders. In collaboration with a specialty pharmaceutical firm, we developed a novel biologic drug, VAL0417, that degrades these glucose aggregates and has a distinct mechanism from other therapies in clinical pipelines. VAL0417 is an antibody-enzyme fusion that combines a cell targeting domain with an enzyme that degrades PGBs. This fusion provides outstanding cell penetration due to targeting a ubiquitous cell surface protein in the CNS that facilitates the uptake of VAL0417. Our previous work shows that VAL0417 can safely be administered in mice, degrades PGBs of Lafora disease (LD), and improves LD pathology. Here we parsospeossem ethnets pnreeecdliendic atol validate VAL0417 as an effective AD treatment. We will first demonstrate that VAL0417 degrades AD-PGBs in vivo. Next, we will define the impact of VAL0417 on AD-associated neurodegeneration and also perform metabolomic analyses to identify surrogate endpoints or features to detect responses to therapy. Finally, we will assess VAL0417 for improvements in memory-associated behavioral assays in rodent AD models We filed a method-of-use provisional patent (#62/987,208) for the use of VAL0417 in AD. Companies have expressed interest in licensing use through us and supporting the translational effort to test efficacy in AD patients and then into clinical trials. Our team has extensive experience with diseases related to PGBs and has unique expertise to perform the work outlined in this proposal. We expect to show that by degrading AD-PGBs, VAL0417 will slow neurodegeneration and improve cognition in AD models and will generate the preclinical data needed to move the technology into commercial partnerships.