Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the DMD gene, leading to a loss of functional dystrophin protein in skeletal, diaphragm, and cardiac muscles. Current genetic medicine approaches to restore dystrophin expression rely on viral delivery of truncated micro-dystrophin constructs or exon-skipping oligonucleotides, which generate shortened DMD proteins with limited functionality and durability. RIPPLE (Remote Induction of Pulsed Pressure Lateral to Energy) is an advanced, proprietary ultrasound-mediated delivery technology that enables efficient, redosable, targeted, and safe delivery of a diverse range of genetic medicine modalities with broad biodistribution across tissues, including skeletal, cardiac, and diaphragm muscles.
We have developed a 14 kilobase DNA vector expressing full-length human dystrophin protein under control of a muscle specific promoter and tested this construct in the human iPSC derived DMD myocytes caring clinically relevant mutations. These results demonstrated functional full-length DMD protein expression across all DMD genetic backgrounds tested. Subsequent RIPPLE-mediated delivery of the full-length DMD vector in multiple rodent DMD models showed robust functional expression of the DMD transgene with broad biodistribution across skeletal muscle fibers. Long-term studies confirmed durable expression of the human DMD protein, with the ability to redose.
To confirm the translatability of RIPPLE technology for delivering the full-length DMD transgene to major muscle groups affected in DMD, including skeletal, cardiac, and diaphragm muscles, studies were conducted in non-human primates. Efficient transgene delivery was observed across all muscle targets, demonstrating robust, targeted, durable, and safe transgene expression with broad biodistribution.
These results establish RIPPLE as an efficient and scalable technology for the delivery of genetic medicine payloads allowing robust expression of functional human full-length dystrophin protein in the muscle groups affected in DMD and provides a foundation for advancing next-generation therapeutic strategies with broad applicability across multiple forms of muscular dystrophy.