LB: Development of mRNA Therapeutic Delivering Full-length dystrophin for Duchenne Muscular Dystrophy


Pre-Clinical Research

Poster Number: T428


Minoru Ko, MD, PhD, Elixirgen Therapeutics, Inc., Tomokazu Amano, PhD, Elixirgen Therapeutics, Inc., Misa Amano, Elixirgen Therapeutics, Inc., Maria Badiola, MD, Elixirgen Therapeutics, Inc., Akihiro Ko, Elixirgen Therapeutics, Inc., Priyanka Ray, PhD, Elixirgen Therapeutics, Inc., Adrian Salmon, Elixirgen Therapeutics, Inc., Hong Yu, Elixirgen Therapeutics, Inc.

The current set of approved drugs for Duchenne muscular dystrophy includes four exon-skipping drugs and one AAV-microdystrophin drug that supplements a missing dystrophin protein with its shortened version. It is conceivable that delivery of a normal, full-length dystrophin protein would address issues seen with these other dystrophin replacement approaches. For example, normal dystrophin would potentially more fully restore muscle function and exhibit a longer half-life in muscle. We have recently developed an mRNA with a proprietary 5’- and 3’-UTR design, called Bobcat mRNA(TM), which has enabled successful generation of mRNA encoding a full-length human dystrophin protein (mRNA-DMD). We first demonstrated the production of a human dystrophin protein in vitro by transfecting mRNA-DMD to cultured human cells. We have also shown the production and proper localization of a human dystrophin protein in skeletal muscles by injecting mRNA-DMD into the skeletal muscles of BALB/c mice. Finally, we have successfully demonstrated the functional recovery of muscle strength in D2.mdx mutant mice, a mouse model for Duchenne muscular dystrophy, by a grip strength meter. We first showed that six weekly injections of mRNA-DMD to the forearm muscles restored the peak muscle strength of the forearm to the level of wild type DBA/2 mice. We then showed that a single injection of mRNA-DMD to the forearm muscles can recover muscle strength in D2.mdx mutant mice. The result also indicates that the produced DMD proteins were stable and remained in the injection site for at least 3 weeks. For the mRNA-DMD injected group, there were no safety findings associated with either the injection or the treatment. These results suggest the possibility of delivering an mRNA encoding a full-length human dystrophin for local and ultimately systemic muscle therapy, which may offer a potential novel complement or replacement for the current therapies for the Duchenne muscular dystrophy.