Bifunctional Intrabodies to Lower Tau
Principal Investigator: David C. Butler, PhD
Neural Stem Cell Institute, Regenerative Research Foundation
Currently, there are no treatments available stopping or delaying the progression of tauopathies. In collaboration with the tau consortium, we have created a large collection of induced pluripotent stem cell (iPSCs) lines from patients with familial dementias due to mutations in the MAPT gene encoding tau. Using this collection, we have created iPSC models of tauopathies recapitulating human disease phenotypes such as the accumulation of hyperphosphorylated misfolded tau. The goal of this drug discovery proposal is to develop therapeutic agents preventing tau accumulation and associated death of brain cells with novel antibody-based reagents (termed intrabodies). Intrabodies are antibodies expressed within cells, which is important as pathological tau accumulation is largely intracellular. They are highly selective for tau, and we have engineered them to target tau for degradation using the cell’s normal clearing process. Our central hypothesis is targeted degradation of tau protein will reduce the amount of tau available to misfold and thus reduce cell death. We have identified 3 candidate bifunctional anti-tau intrabodies promoting tau degradation. Here we propose to determine the efficacy of human anti-tau-PEST intrabodies to counteract tau related pathology and gene network dysregulation observed in PSP patients. To accomplish this, patient specific iPSC-derived cortical neurons and glia with a MAPT N279K mutation will be used. At the end of the funding period, we will have determined whether intrabody-based proteasome targeting can effectively reduce tau levels and whether these approaches enhance neuronal survival. These characterized intrabodies can then be tested for their capacity to alter signs of tau related pathology in future studies in animal models.