Duchenne Muscular Dystrophy (DMD) is a devastating progressive muscle wasting disorder caused by mutations on the DMD gene that result in the complete absence of its protein product, dystrophin. Studies involving Adeno-associated viral (AAV) vector-mediated gene transfer approaches highlight the challenges the immune system can impose when it encounters “non-self” dystrophin epitopes. As an alternative, our lab relies on utrophin, a dystrophin paralog that retains most of dystrophin’s structural and binding elements. Importantly, normal thymic expression in DMD subjects should protect utrophin by central immunologic tolerance. Here I describe how an AAV vector containing a codon optimized truncated utrophin transgene (AAV-μUtrophin) is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models of DMD. Following systemic administration of AAV-μUtrophin in neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, μUtrophin non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of μUtrophin in the deletional-null German shorthaired pointer canine model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed μDystrophin. These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile. Our latter immunological findings would become the biological premise for a prospective vaccine against SARS-CoV-2 virus, the agent responsible for the ongoing global COVID-19 pandemic. SARS-CoV-2 relies on its major surface antigen, Spike protein, to gain access into host cells and therefore is a key target for vaccines. A single intramuscular injection in adult C57Bl/6 mice of a synthetic Spike protein (M8B), driven by a CMV promoter and packaged in an AAV vector (AAV-CMV-M8B), resulted in transient expression and a robust cell mediated immune response against M8B. Together these findings demonstrate how an AAV-mediated gene transfer approach can be used to provide a therapeutic effect and can be tuned to drive or steer away an immune response against vector encoded antigens.