The advent of genomic editing technology offers the tantalizing promise of precisely treating a variety of disease states at the genetic level. CRISPR-Cas has democratized this capability in laboratory settings across the world. However, developing these exciting tools into therapies appropriate for clinical use involves several challenges including the potential recognition of foreign components such as the Cas effector proteins by the adaptive immune system which may limit the effectiveness of gene therapy. Here I approach this problem by first characterizing the immune response to AAV-delivered CRISPR-Cas in a mouse model targeting the PCSK9 protein, known to play a major role in atherosclerotic disease. Next, I propose and test a method to enable redosing by leveraging immune orthogonal components of AAV-CRISPR-Cas therapeutics, systematically defining the capability of this approach to avoid immune-mediated inhibition of therapeutic efficacy. Finally, in an effort towards building a single deimmunized Cas9 protein usable across diverse contexts while circumventing pre- existing immunity, I develop a scalable and portable long-range multiplexed protein engineering platform to progressively de-immunize target proteins by abolishing the most immunogenic MHC-restricted epitopes without disrupting protein function. By applying this technique to Cas9, I identify a Cas9 variant with 7 simultaneously deimmunized epitopes that retains near wild-type functionality for both direct editing and gene activation/repression. Taken together, this work represents a meaningful step towards unlocking the potential to precisely edit genomes and gene expression in the clinical setting.