Exon Skipping and Inclusion Therapies

Ngoc Lu-Nguyen, George Dickson, Alberto Malerba, Lu-Nguyen, Ngoc, Dickson, George, Malerba, Alberto

Using antisense oligonucleotides (AOs) to reframe mutated dystrophin, a recently developed therapeutic approach for Duchenne muscular dystrophy (DMD) named exon skipping, is considered among the most promising treatments for DMD patients. The development of this strategy is rapidly moving forward and the AO designed to skip exon 51 has received accelerated approval in the USA. However the strong complexity of the DMD pathology suggests that at least in older patients, where the muscle structure is almost completely compromised and the muscle is wasted and significantly infiltrated with fat and connective tissue, combined therapeutic approaches should be developed to approach the disease more effectively. Here we describe the methodology for the systemic intravenous delivery of AOs targeting dystrophin and myostatin in mdx mice, a DMD mouse model, in order to express dystrophin while downregulating myostatin, aiming for an increase in the muscle size and muscle strength. Furthermore the most relevant functional analyses to be performed in living mice and the most informative histopathological and molecular assays to evaluate the effect of this treatment are detailed.