In Duchenne Muscular Dystrophy (DMD), loss of the dystrophin protein causes continuous and chronic muscle injury with ineffective repair and regeneration, leading to fibrofatty replacement of muscle, progressive weakness and premature death. Recent gene replacing treatments through AAV micro-dystrophin gene transfer (GT) or exon skipping strategies restore dystrophin at the sarcolemma membrane and show clinical improvement. However complete resolution of muscular dystrophy is not observed. We seek to understand the cellular mechanisms of DMD and response to gene replacement strategies to identify barriers to successful GT response and complementary strategies to enhance therapeutic efficacy. We have performed single nuclei RNA sequencing on skeletal muscle biopsies and single cell RNA sequencing of muscle-derived mononuclear cells and peripheral blood mononuclear cells (PBMCs) to comprehensively observe the dystrophic niche. In total, we have generated 804,392 single nucleus, 938,170 mononuclear cell, and 288,430 PBMC transcriptomes including individuals biopsied from 6 months to 6 years post GT. Preliminary results suggest that clinical response to gene replacement may be limited by continued aberrant signaling among contractile and non-contractile muscle cells that perpetuates a maladaptive, hyperinflammatory innate immune memory in skeletal muscle, impairing regeneration and driving ongoing fibrosis. Together, our data provides a unique insight into muscle cell dynamics at a single cell resolution before and after dystrophin replacement and uncovers potentially predictive biomarkers and druggable targets to enable more complete resolution of muscular dystrophy.