Duchenne Muscular Dystrophy (DMD) therapy deletes let-7c miRNA binding sites using CRISPR-Cas9 based genome editing and AAV based delivery.

Duchenne Muscular Dystrophy (DMD) is a fatal disease characterized by progressive muscle degeneration and weakness that affects 1 in 3,500 live-born males worldwide, and which ultimately causes death in the twenties due to respiratory or cardiac failure. It is caused by mutations in the DMD gene leading to an absence or severe reduction of dystrophin, a protein that helps keep muscle cells intact. There is currently no cure for DMD and all dystrophin-based approaches are associated with immunoreactivity limiting their long-term efficacy.

Dr. Khurana and colleagues at University of Pennsylvania developed a method to upregulate utrophin, a dystrophin homolog protein, using CRISPR-Cas9 based genome editing and AAV-based delivery. The inventors have previously demonstrated in a mouse model that inhibiting the interaction between the let-7c miRNA and utrophin gene, which normally acts to represses expression, is able to increase utrophin expression and functionally rescue dystrophic phenotype. This discovery led to the present method that genomically edits the microRNA binding sites in the utrophin gene to ultimately upregulate utrophin expression.

Unlike dystrophin-targeting gene therapy, this method is particularly attractive for therapeutic strategies, as extremely high levels of utrophin are not associated with toxicity or immunoreactivity.

• No immunoreactivity associated with high levels of utrophin in vivo
• Rescues dystrophic phenotype

• Therapeutic for Duchenne Muscular Dystrophy