Curt Mazur, Berit Powers, Kenneth Zasadny, Jenna M Sullivan, Hemi Dimant, Fredrik Kamme, Jacob Hesterman, John Matson, Michael Oestergaard, Marc Seaman, Robert W Holt, Mohammed Qutaish, Ildiko Polyak, Richard Coelho, Vijay Gottumukkala, Carolynn M Gaut, Marc Berridge, Nazira J Albargothy, Louise Kelly, Roxana O Carare, Jack Hoppin, Holly Kordasiewicz, Eric E Swayze, Ajay Verma
Intrathecal (IT) delivery and pharmacology of antisense oligonucleotides (ASOs) for the CNS have been successfully developed to treat spinal muscular atrophy. However, ASO pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly understood in the IT compartment. We applied multimodal imaging techniques to elucidate the IT PK and PD of unlabeled, radioactively labeled, or fluorescently labeled ASOs targeting ubiquitously expressed or neuron-specific RNAs. Following lumbar IT bolus injection in rats, all ASOs spread rostrally along the neuraxis, adhered to meninges, and were partially cleared to peripheral lymph nodes and kidneys...
October 17, 2019: JCI Insight