Oligonucleotide-based therapies have potential for treating a range of inherited neuromuscular disorders via modulating gene expression e.g. via splice modulation or RNA silencing. The classical example is Duchenne muscular dystrophy (DMD), where modulation of pre-mRNA splicing of the DMD gene can restore a viable reading frame and the expression of functional protein. This approach is currently being evaluated in clinical trials. However, a major challenge in the application of such approaches to neuromuscular disease is poor delivery to affected tissues including skeletal muscle, heart and to the nervous system across the blood brain barrier. We have developed a range of peptide- and extracellular vesicle-based platform technologies to overcome this challenge. Peptide-oligonucleotide compounds provide greatly improved delivery and enhanced potency and are being developed for future clinical applications in both DMD and for other neuromuscular disorders, such as spinal muscular atrophy. Future prospects will be discussed.
References
1. Fairclough RJ, Wood MJ, Davies KE. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nature Reviews Genetics 2013 Jun;14(6):373-8
2. Hammond SM, Hazell G, Shabanpoor F, Saleh AF, Bowerman M, Sleigh JN, Meijboom KE, Zhou H, Muntoni F, Talbot K, Gait MJ, Wood MJ. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):10962-7
3. EL Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nature Reviews Drug Discovery 2013 May;12(5):347-5
4. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology 2011 Apr;29(4):341-5