Gene-targeted therapies have made tremendous advances in recent years for neurological diseases where the therapeutic goal is to lower levels of a toxic protein. In these contexts, therapeutics bind to target RNA and promote degradation of the RNA transcript. However, many neurological disorders, including subsets of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), are caused by mutations that result in haploinsufficiency, whereby one copy of the gene is insufficient to preserve normal function. For example, mutations in TBK1 (TANK-binding protein kinase 1) that result in loss of TBK1 function cause FTD/ALS. Current methods to increase protein levels, including viral-mediated delivery or direct protein addition, are limited. Viral approaches lack regulatability of expression, which may have detrimental consequences for a target like TBK1 that regulates autophagy, immune signaling, cell proliferation, and metabolism. Direct protein delivery allows some titration but is unlikely to induce sufficient expression to restore function. To overcome these limitations and develop a gene-targeted therapeutic for TBK1 in FTD/ALS, we developed antisense oligonucleotides (ASOs) against regulatory sequences within the TBK1 gene to boost TBK1 protein expression. Treatment with this TBK1-upregulating ASO in reporter assays and human cells leads to increased levels of TBK1 by ~1.5-fold, levels that would be expected to restore protein to near-normal expression under haploinsufficiency conditions. Our proposal aims to optimize these ASOs to increase TBK1 protein and restore function in FTD/ALS caused by TBK1 haploinsufficiency. Given recent successes of ASO therapeutics for neurodegenerative diseases, TBK1 ASOs could quickly advance to clinical trial as a novel therapy for TBK1-FTD/ALS. Further, we are developing this approach as a platform applicable to other haploinsufficiency disorders (e.g., progranulin FTD) or to increase growth factor proteins or transcription factors. Thus, learnings from this work can be leveraged for future ASO therapeutics development.