Despite major advances in RNA therapeutics, delivery to skeletal and cardiac muscle remains a central barrier to treating Duchenne muscular dystrophy (DMD) and related cardiomyopathies. Current phosphorodiamidate morpholino oligonucleotide (PMO) and antibody-oligonucleotide conjugate (AOC) approaches exhibit limited tissue penetration, transient efficacy, and manufacturing complexity.
We present a next-generation Locked Nucleic Acid (LNA) antisense mixmer platform that combines AI-guided oligonucleotide design with validated medicinal chemistry to generate potent, durable, and systemically deliverable RNA therapeutics without lipid or viral vectors. The platform integrates thermodynamic modeling, off-target and toxicity prediction, and manufacturability scoring to rapidly identify development-ready candidates.
As a lead example, anti-miR-128 LNA ASO mixmers demonstrate broad tissue exposure, strong target knockdown, and improved muscle function following subcutaneous dosing in preclinical models. Efficacy was observed across multiple disease contexts, including DMD, post-myocardial-infarction heart failure, and smoke-induced cardiac dysfunction, highlighting a shared molecular mechanism of muscle and cardiac degeneration modulated by miR-128.
The platform’s inherent scalability and favorable CMC profile enable cost-effective GMP production and support multiple partnering models, including asset generation for pharma collaborators. Relative to PMO or AOC modalities, LNA ASO mixmers offer enhanced potency, extended duration of action, simple subcutaneous delivery in saline, superior manufacturability, and low COGS, positioning this chemistry as a clinically and commercially viable solution for precision RNA medicine.
Together, these advances establish the LNA ASO mixmer platform as a versatile, partnership-ready engine for RNA-based therapeutics targeting skeletal and cardiac muscle disease.