TY - JOUR AU - Mazur, Curt AU - Powers, Berit AU - Zasadny, Kenneth AU - Sullivan, Jenna M. AU - Dimant, Hemi AU - Kamme, Fredrik AU - Hesterman, Jacob AU - Matson, John AU - Oestergaard, Michael AU - Seaman, Marc AU - Holt, Robert W. AU - Qutaish, Mohammed AU - Polyak, Ildiko AU - Coelho, Richard AU - Gottumukkala, Vijay AU - Gaut, Carolynn M. AU - Berridge, Marc AU - Albargothy, Nazira J. AU - Kelly, Louise AU - Carare, Roxana O. AU - Hoppin, Jack AU - Kordasiewicz, Holly AU - Swayze, Eric E. AU - Verma, Ajay T1 - Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging PY - 2019/10/17/ AB - 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. Rapid association with the pia and arterial walls preceded passage of ASOs across the glia limitans, along arterial intramural basement membranes, and along white-matter axonal bundles. Several neuronal and glial cell types accumulated ASOs over time, with evidence of probable glial accumulation preceding neuronal uptake. IT doses of anti-GluR1 and anti-Gabra1 ASOs markedly reduced the mRNA and protein levels of their respective neurotransmitter receptor protein targets by 2 weeks and anti-Gabra1 ASOs also reduced binding of the GABAA receptor PET ligand 18F-flumazenil in the brain over 4 weeks. Our multimodal imaging approaches elucidate multiple transport routes underlying the CNS distribution, clearance, and efficacy of IT-dosed ASOs. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.129240 VL - 4 IS - 20 UR - https://doi.org/10.1172/jci.insight.129240 PB - The American Society for Clinical Investigation ER -