Phase of Development: Lead Optimization
Mechanism of Action: Tau Phosphorylation and Posttranslational Modifications
Compound Type/Modality: Antibody/Biologic
Developing Biomarkers and Vectorized Immunotherapy Targeting Acetylated Tau
Li Gan, PhD
Director, Helen and Robert Appel Alzheimer's Disease Research Institute
Cornell Weill Medical Institute (New York, NY)
The overall objective of the proposal is to establish ac-tau-based biomarkers for characterizing different tau strains, and to develop AAV-based vectorized immunotherapy targeting acetylated tau. Previous studies from our lab and others established important pathogenic roles of acetylated tau. More recent cryo-EM study combined with mass-spec analyses established the tau fibril structure at atomic levels and confirmed that the core component of tau seeds are almost exclusively acetylated or ubiquitinated, suggesting that acetylation/ubiquitination at different sites is likely to mediate strain diversity in tauopathy. To comprehensively evaluate the different strains characterized by different ac-K sites, we will generate a panel of monoclonal antibodies targeting all the ac-K sites on tau identified in AD brains (Aim 1). Passive immunotherapy is being developed into therapeutic strategies against AD. One major challenge for passive immunotherapy for targets in the CNS is the poor permeability of antibodies across the blood brain barrier. Expression of vectorized single-chain variable fragments (scFVs) could overcome this challenge. There are several distinct advantages of scFVs; the objective is our Aim 2 is to generate and select single-chain variable fragments (scFVs) against ac-tauK174 to express in the brain and to test its in vivo efficacy in tauopathy mice. Completion of Aim 1 and Aim 2 will greatly advance therapeutic development of ac-tau immunotherapy.
The overall objective of the proposal is to advance therapeutic development of tau immunotherapy by establishing biomarkers to characterize different tau strains, and to develop AAV-based vectorized immunotherapy targeting acetylated tau to achieve sustained and enhanced antibody exposure in the brain.