Research Area #4: Biotherapeutics to Alter Immunoproteostasis in Neurodegenerative Proteinopathies
We have extensive experience in developing recombinant antibodies against Ab, tau, and a-synuclein. Although we have conducted passive immunotherapy when justified, in most cases we use rAAV vectors to deliver the biotherapeutic that enable the transgene encoding the biotherapeutic to be expressed directly in the brain. Current work is focused on refining effector functions of the recombinant antibodies. We also deliver both ligands and decoy receptors that often provide a biological agonists antagonist paradigm to explore relatively understudies immune pathways in relevant models of neurodegenerative proteinopathies. These later studies have helped to overturn dogma in the field that activation of the immune system in the brain is always harmful. Instead, we find that factors that activate the immune system reduce Abeta deposition, and those that inhibit immune activation actually promote amyloid deposition and worsen overall phenotypes.
Key Publications: P. Chakrabarty et al., J Exp Med 215, 2247-2264 (2018). Y. Levites et al., J Neurosci 26, 11923-11928 (2006);M. S. Goodwin et al., Mol Ther 29, 859-872 (2021). Y. Levites et al., Mol Neurodegener 16, 32 (2021); J. I. Ayers et al., Mol Ther 23, 53-62 (2015); P. Chakrabarty et al., Neuron 85, 519-533 (2015).
