ABSTRACT Differences in our individual genomes give rise to most of human diversity. This uniqueness of every human being underpins the purpose of precision medicine, which posits that disease prediction, diagnosis, and treatment for each individual is based on personal genomic variations. The rapid advancement of genome editing technology has led to numerous promising preclinical studies in muscular dystrophies (MDs). These studies were performed in inbred animals, with mice being the most extensively used models, in which the component of genetic diversity has been largely ignored. Genetically speaking, developing a therapeutic intervention in a single inbred mouse strain is the equivalent of treating a single patient and limits the generalizability and translatability of the results into human applications. Failure to anticipate the genetic diversity in patient populations will confound future clinical trials and may lead to adverse outcomes. In this NIH Innovator Award, my goal is to revolutionize the conventional method by which we develop genetic therapy to reflect diverse and more realistic human populations. First, I will integrate the naturally occurring genetic reference panel into a model harboring MD-causing mutation to better simulate diverse patient population and elevate its translational value. I will use this innovative model to investigate whether the introduced genetic variation profoundly modifies the neuromuscular presentations. Furthermore, I will study the implications of genetic variation on the safety and efficacy of therapeutic genome editing approaches that I have developed throughout my career. As we move closer towards designing clinical treatment that is based on an individual's biological makeup, it is imperative that we understand how inherited variability influences disease phenotypes, how it can confound experiments, and how it can be exploited to reveal new truths about disease biology. Using MD as a starting point, successful outcome of this project can be integrated into a framework for future therapeutic developments in different diseases and across patient populations.