Project 1.  Developing antisense oligonucleotide-mediated therapy towards clinical trials for Duchenne muscular dystrophy. 

Qi Lu PhD.  Carolinas Research Institute, North Carolina

            We have shown that antisense therapy is able to induce therapeutic amount of dystrophin with functional improvement via local intramuscular injection. Systemic delivery of AONs can also induce specific exon skipping and restoration of dystrophin expression in body-wide skeletal muscles with therapeutic levels of dystrophin in some of the skeletal muscles. These results indicate that antisense therapy is a realistic possibility for the treatment of DMD.

            However, the dispersed nature of DMD requires induction of therapeutic levels of dystrophin in ideally all skeletal and cardiac muscles. In addition, dystrophin induction by antisense oligonucleotides, lasting for 2 to 3 months after injection of 2OMeAON, is transient. Non-traumatic means for regular administration of AONs are required to maintain therapeutic levels of dystrophin throughout the life of DMD patients. The potential toxicity of these chemistries for AONs following systemic delivery has to be assessed before they are subjected to a costly comprehensive toxicology test. Furthermore, AON sequences specific for skipping targeted exon of the human dystrophin gene have to be established and their toxicity assessed before future clinic trials.

            Our goal is therefore to develop the antisense therapy into a safe, effective, and pharmacological treatment for the majority of DMD patients. We conclude that such a goal is attainable through further investigation of existing AON chemistry, design of effective oligonucleotide sequences specific for skipping exons in human dystrophin gene and the establishment of effective delivery systems of AONs.  This project, as a phase I trial, aims to establish effective chemistry for the synthesis of AON, effective AON sequences for skipping of 2 exons in human dystrophin gene for correction of a group of DMD mutations, and effective regime for delivery of AON into muscles. These parameters will be critical for design of clinical trials and full –scale toxicology test of the reagents.