| Literature DB >> 30531949 |
Ningyan Hu1,2, Layal Antoury1,2, Timothy M Baran3, Soumya Mitra3, C Frank Bennett4, Frank Rigo4, Thomas H Foster3, Thurman M Wheeler5,6.
Abstract
During drug development, tissue samples serve as indicators of disease activity and pharmacodynamic responses. Reliable non-invasive measures of drug target engagement will facilitate identification of promising new treatments. Here we develop and validate a novel bi-transgenic mouse model of myotonic dystrophy type 1 (DM1) in which expression of either DsRed or GFP is determined by alternative splicing of an upstream minigene that is mis-regulated in DM1. Using a novel in vivo fluorescence spectroscopy system, we show that quantitation of the DsRed/GFP ratio provides an accurate estimation of splicing outcomes in muscle tissue of live mice that nearly doubles throughput over conventional fluorescence imaging techniques. Serial in vivo spectroscopy measurements in mice treated with a C16 fatty acid ligand conjugated antisense (LICA) oligonucleotide reveal a dose-dependent therapeutic response within seven days, confirm a several-week duration of action, and demonstrate a two-fold greater target engagement as compared to the unconjugated parent oligonucleotide.Entities:
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Year: 2018 PMID： 30531949 PMCID： PMC6286378 DOI： 10.1038/s41467-018-07517-y
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919