Warner, M. J.; Kelly, L.; Thakur, R.; Ravichandran, M.; Tomar, D.; Nidhi, N.; Tamraparni, V.; Govindaraj, E.; Samji, P.; Krishna, M.; Kulkarni, A. S.; LEVY, M.

Oligonucleotide based therapeutics continue to rise as a significant class of medicines for the treatment of human disease. However, achieving delivery to non-hepatic tissues remains a challenge in the field. While substantial advances have been realized, largely through the use of antibody or protein based targeting agents to tissues including muscle and the CNS, these large protein agents present complications in synthesis and carry the potential for immune responses. In an effort to identify a simpler, smaller and robust means of delivery, we have generated and evaluated aptamers targeting the human transferrin receptor (hTfR) for the delivery of both ASO and siRNA cargoes to muscle. Using a fully backbone modified anti-TfR aptamer, 36 nt in length, that binds hTfR and does not compete for binding with the natural ligand, transferrin, we evaluated the ability to deliver ASOs to skeletal muscle following systemic delivery. Using optimized linker chemistry, aptamer-ASO conjugates led to >50% target gene knockdown in muscle tissue for up to 42 days following a single dose at 3 mg/kg ASO (~11 mg/kg total drug) in mice. Taken as a whole, these results offer significant promise for the use of aptamers in the development of future therapeutics.