Title
Feasibility of SPECT-CT imaging to study the pharmacokinetics of antisense oligonucleotides in a mouse model of Duchenne muscular dystrophy
Author
van de Steeg, E.
Läppchen, T.
Aguilera, B.
Jansen, H.T.
Muilwijk, D.
Vermue, R.
van der Hoorn, J.W.
Donato, K.
Rossin, R.
de Visser, P.C.
Vlaming, M.L.H.
Publication year
2017
Abstract
Antisense oligonucleotides (AONs) are promising candidates for treatment of Duchenne muscular dystrophy (DMD), a severe and progressive disease resulting in premature death. However, more knowledge on the pharmacokinetics of new AON drug candidates is desired for effective application in the clinic. We assessed the feasibility of using noninvasive single-photon emission computed tomography-computed tomography (SPECT-CT) imaging to determine AON pharmacokinetics in vivo. To this end, a 2′-O-methyl phosphorothioate AON was radiolabeled with 123I or 111In, and administered to mdx mice, a rodent model of DMD. SPECT-CT imaging was performed to determine AON tissue levels, and the results were compared to data obtained with invasive analysis methods (scintillation counting and a ligation-hybridization assay). We found that SPECT-CT data obtained with 123I-AON and 111In-AON were qualitatively comparable to data derived from invasive analytical methods, confirming the feasibility of using SPECT-CT analysis to study AON pharmacokinetics. Notably, also AON uptake in skeletal muscle, the target tissue in DMD, could be readily quantified using SPECT-CT imaging, which was considered a particular challenge in mice, due to their small size. In conclusion, our results demonstrate that SPECT-CT imaging allows for noninvasive characterization of biodistribution and pharmacokinetics of AONs, thereby enabling quantitative comparisons between different radiolabeled AON drug candidates and qualitative conclusions about the corresponding unmodified parent AONs. This technology may contribute to improved (pre)clinical drug development, leading to drug candidates with optimized characteristics in vivo.
Subject
Life
MSB - Microbiology and Systems Biology
ELSS - Earth, Life and Social Sciences
Nutrition
SPECT imaging
Antisense oligonucleotides
RNA-based therapeutics
Duchenne muscular dystrophy
Antisense oligonucleotides
Antisense oligonucleotide i 123
Antisense oligonucleotide in 111
Indium 111
Iodine 123
Tracer
Unclassified drug
Animal experiment
Animal model
Animal tissue
Controlled study
Drug distribution
Drug half life
Drug tissue level
Drug uptake
In vivo study
Male
Mouse
Mouse model
Nonhuman
Single photon emission computed tomography-computed tomography
Skeletal muscle
Target tissue
To reference this document use:
http://resolver.tudelft.nl/uuid:69f24d6e-b03d-4e05-ac81-8dac4d8771e3
DOI
https://doi.org/10.1089/nat.2016.0649
TNO identifier
756765
Source
Nucleic Acid Therapeutics, 27 (4), 221-231
Document type
article