Abstract Body: Aortic aneurysm (AA) is a life-threatening vascular disorder that often progresses silently until rupture or dissection (AD), which carries >80% mortality and accounts for over 150,000 deaths globally each year. Despite the severe outcomes, no pharmacological treatments exist, and surgical repair remains the only therapeutic option. Our prior work demonstrated that base editing of a pathogenic ACTA2 mutation restored smooth muscle cell (SMC) function and attenuated AA/AD in a mouse model. However, over 70% of AA cases are sporadic with no known genetic mutations, limiting the application of mutation-based gene correction. We aimed to develop a broadly applicable base editing strategy targeting CaMKIIδ, a multifunctional kinase implicated in cardiovascular signaling, whose role in vascular disease is not well characterized. Using genetic mouse models, we demonstrate that CaMKIIδ deletion confers significant protection against angiotensin II (Ang II)-induced AA/AD development. In human iPSC-derived SMCs, loss of CaMKIIδ autophosphorylation induces a differentiated, contractile phenotype and preserves expression of key transcriptional regulators MYOCD and MEF2C, even under inflammatory stress. To enable therapeutic targeting, we deployed adenine base editing (ABE8e-SpRY) together with a single guide RNA (sgRNA) to disrupt CaMKIIδ expression via splice acceptor site (SAS) editing of exon 4, inducing exon skipping and frameshift-mediated knockdown. Additionally, we designed a second sgRNA for use with ABE8e-SpCas9-NG to selectively block CaMKIIδ autophosphorylation while preserving protein expression. Both base editing approaches showed high on-target efficiency in vitro. To enable in vivo delivery, we packaged base editors and validated sgRNAs into AAV9 vectors, a clinically relevant system for cardiovascular gene therapy. We are evaluating therapeutic efficacy in mouse models of AA/AD, assessing aortic integrity, smooth muscle phenotype, and molecular readouts of CaMKIIδ inhibition. Our findings identify CaMKIIδ as a central regulator of the smooth muscle phenotype and aortic pathology. By applying CRISPR base editing to modulate CaMKIIδ expression and activity, we hope to develop a mutation-independent gene therapy strategy with the potential to transform the treatment landscape for AA and AD.