Science Tokyo succeeds in treating muscular dystrophy using mRNA therapy

A research group led by Professor Keiji Itaka from the Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research at the Institute of Science Tokyo (Professor of the Center for Infectious Disease Education and Research at the University of Osaka), Director Yoshitsugu Aoki at the National Center of Neurology and Psychiatry's National Institute of Neuroscience, and Associate Professor Takashi Yamada from Sapporo Medical University's School of Health Sciences has announced successful treatment of Duchenne muscular dystrophy (DMD) model mice using mRNA therapeutics. The team confirmed that administration using their originally developed "nanomicelle-type mRNA carrier" with the hydrodynamiclimb vein (HLV) method enabled delivery without causing inflammation or muscle damage. Practical application of this treatment is awaited. The group's findings were published in the March 6 issue of the international academic journal Advanced Science.

DMD is a hereditary disease that primarily affects males and has no curative treatment. It progresses with muscle tissue destruction and decreasing muscle strength due to mutations in the dystrophin protein gene essential for maintaining muscle structure. Aoki's team previously developed an exon-skipping therapy using antisense nucleic acids for DMD, but its effectiveness was limited to specific gene mutations. In the past, the research group confirmed symptom improvement in DMD-related autism spectrum disorder by administering mRNA therapeutics to the brain.

In this study, the research group used mRNA for the "PGC-1α" gene, a protein reported to improve muscle symptoms in DMD by enhancing mitochondrial synthesis and metabolic activity. Using their originally developed "nanomicelle-type mRNA carrier" based on synthetic polymers, they administered the treatment to the knees of DMD disease model mice (mdx mice) using the HLV method. It was successfully delivered to a wide range of muscle cells with minimal inflammation. When the mice were evaluated one week after administration, the group using the nanomicelle-type mRNA carrier showed significantly reduced exercise-induced muscle weakness and post-exercise muscle tissue damage compared to the groups that received saline solution, mRNA alone, or LNP (lipid nanoparticle) administration. Gene expression analysis also confirmed increased expression of genes related to mitochondrial activity, muscle activity, and muscle hypertrophy.

Typically, mRNA vaccines use LNPs for delivery and are administered via intramuscular injection. However, LNPs can cause inflammation due to immune reactions, and intramuscular injections are particularly unsuitable for treating this disease which already involves muscle damage. In contrast, the HLV method involves tying a tourniquet at the proximal location, administering through the great saphenous vein, and waiting five minutes, which can suppress inflammation. However, the applicable sites are limited. Indeed, while LNP administration showed related gene expression, it also caused high inflammatory responses and showed no therapeutic effect.

Itaka commented: "mRNA therapeutics using nanomicelle-type mRNA carriers can be applied not only to muscles but also to other targets. We are currently planning clinical trials for osteoarthritis treatment this summer. We hope to realize therapeutic mRNA applications beyond vaccines."

Journal Information
Publication: Advanced Science
Title: Polyplex Nanomicelle-Mediated Pgc-1α4 mRNA Delivery Via Hydrodynamic Limb Vein Injection Enhances Damage Resistance in Duchenne Muscular Dystrophy Mice
DOI: 10.1002/advs.202409065