Jean-Pierre Julien, PhD
Intrabody-based therapy to inhibit TDP-43 interaction with p65 NF-κB
We discovered that an upregulation of TDP-43 in ALS acts as co-activator of nuclear factor-κB (NF-κB) and that this interaction can induce hyperactivity of NF-κB resulting in exaggerated innate immune responses and increased neuronal vulnerability to toxic environment. Here we propose to develop a therapeutic approach based on expression of nuclear intrabodies (antibodies that work inside the cell) against TDP-43 to specifically block its interaction with NF-κB p65. We have generated a hybrid cell line that produces monoclonal antibodies against the RRM1 domain of TDP-43. From these cell lines, we will derive cDNAs encoding single chain antibodies (scFv) that will be used to generate an adeno-associated virus. This virus will encode intrabodies aiming to block TDP-43 interaction with p65 in the nucleus and to alleviate protein aggregation.