Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder marked by lack of dystrophin expression. Symptoms include loss of ambulation, respiratory problems, and cardiac complications with heart failure in their 20s being the leading cause of death. Dystrophin transduces force from the actin cytoskeleton to the extracellular matrix to protect cells during muscle contraction. Restoration of dystrophin expression, addressing the root cause of disease, holds promise in delaying the onset of heart failure. Gene therapy using adeno-associated virus (AAV) is the most efficient method to systemically deliver genes to all the skeletal muscles, diaphragm, and the heart. Despite its high tropism, a few DMD patients have experienced myocarditis due to AAV gene therapy. To capture the inflammatory gene signatures, I transduced DMD cardiomyocytes with AAV and lentivirus. These cardiomyocytes were differentiated from patient-derived induced pluripotent stem cells. Global transcriptional profiling revealed distinct inflammatory signatures in AAV compared to untreated controls. In addition to activating the immune system, AAV has a packaging limit of 4.7 kb, which is much smaller than the 11 kb coding sequence of dystrophin. Split inteins, sequences found in nature that facilitate the ligation of two proteins encoded by independent vectors, can be used to deliver large transgenes that exceed the packaging limit of AAV. I have developed a screening platform to identify split inteins predicted to have low immunogenicity that efficiently splice out of the ligated protein. This split intein screening platform will provide improved methods to deliver large transgenes and attenuating the inflammatory signatures from AAV delivery may provide safer methods for gene therapy.