Virtici LLC

A Novel Antibody That Promotes Neuronal Integrity and Neurogenesis for Treating Alzheimer's Disease - Project Summary Our Goal Is to Develop a Novel Neuron-penetrating Bispecific Antibody That Promotes Neuronal Integrity and Neurogenesis for the Treatment of Ad. in the Us Alone, Over 6 Million Americans Are Currently Living With Ad, With Total Economic Costs Around $355 Billion in 20211. Despite the Staggering Cost, Only a Few Mildly Effective Ad Symptom-treating Drugs Exist. as a Result, Treating and Even Reversing the Effects of Ad Remains a Significant Unmet Need. Pathologically, Ad Is Characterized by the Presence of Neuritic Plaques and Neurofibrillary Tangles in the Brain. the Primary Component of the Extracellular Neuritic Plaques Is the Ss-amyloid Protein (ass), an Approximately 4 Kda Fragment Proteolytically Derived From the Larger Amyloid Precursor Protein (APP)2. a Vast Amount of Literature Has Implicated Ass Accumulation as Being Central to the Progression of Ad, and Inhibiting Ass Production Represents a Promising Strategy for Treating Ad. We Have Generated Two Single-chain Variable Domain Antibody Fragments (SCFV), Asec and Bsec, Which Respectively Promote A-secretase Activity and Block Ss-secretase Activity Toward Amyloid Precursor Protein (APP) by Binding to App at Either the A-site or the SS-SITE3-5. Next, We Generated a Tandem Bispecific Antibody That Combines the Asec and Bsec Scfvs and Showed That It Elevates Levels of Sappa, a Soluble A-secretase- Associated App Fragment, and Decreases Levels of Ass and Sappss, a Soluble Ss-secretase-associated Fragment in Cell Models of AD6. an Apob Tag Was Added to the Bispecific Antibody (called VTC-939), Which Can Facilitate Transfer Across the Blood-brain Barrier (BBB)6-8 and Neuronal Targeting. Using Recombinant Human Adeno- Associated Virus (RAAV) as a Vector Infective to Hepatic Cells, VTC-939 Could Be Secreted Into the Blood and Brain at High Levels. When VTC-939 Was Tested as a Therapeutic in an APP/PS1 Ad Mouse Model, VTC-939 Increased Levels of Sappa, While Decreasing Ass Deposits and Oligomeric Ass Levels. in Addition, VTC-939 Treatment Increased Neuronal Health, Substantially Increased Hippocampal Neurogenesis and Significantly Increased Survival Rates Compared With Untreated MICE9. These Results Indicate That Altering App Processing to Inhibit Toxic Amyloidogenic Ss-site Activity While Simultaneously Promoting Neuroprotective A-secretase Processing Provides Increased Neuronal Benefits and Represents a Promising New Therapeutic Approach for Treating, and Potentially Reversing Ad. Building From This Work, Our Objective Is to Develop VTC-939 as a Novel Neuron-penetrating Antibody That Restores Neuronal Integrity and Promotes Neurogenesis for the Treatment of Ad. the Specific Aims Are to: 1) Produce Antibody Constructs and Establish Quality Control Assays, 2) Determine the Optimal Effective Dose of VTC-939 to Promote Neuronal Integrity, Neurogenesis and Longevity in the APP/PS1 Ad Mouse Model, and 3) Generate Acute Toxicology and Biodistribution Profiles for VTC-939 in Normal Healthy Mice. a Therapy That Can Safely and Effectively Promote Neuronal Integrity and Neurogenesis Would Provide a Significant Advancement for a Clear Unmet Medical Need.