Systemic Delivery of Antisense Oligomer in Animal Models and Its Implications for Treating DMD

Antisense oligomer (AO)-mediated splicing modulation for treating DMD demands a systemic administration of AOs as pharmacological drugs to achieve effective prevention of disease progression and to improve quality and longevity of patient life. Three routes, namely, intravenous injection (IV), intraperitoneal injection (IP), and subcutaneous injections (SC), of systemic delivery of AOs have been examined in animal models, and two of them, IV and SC, are being applied in the ongoing clinical trials. The main barrier for systemic treatment with unmodified AO of both chemistries, 2′-O methyl Phosphorothioate RNA and phosphorodiamidate morpholino, is the high degree of variation in exon skipping efficiency both between body-wide muscles and within individual muscle seen in mouse models. AO therapy will likely critically depend on adequate dosing regimens to achieve therapeutic effect.