Non-invasive monitoring of alternative splicing outcomes to identify candidate therapies for myotonic dystrophy type 1

Ningyan Hu, Layal Antoury, Timothy M. Baran, Soumya Mitra, C. Frank Bennett, Frank Rigo, Thomas H. Foster and Thurman M. Wheeler ()
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Ningyan Hu: Massachusetts General Hospital
Layal Antoury: Massachusetts General Hospital
Timothy M. Baran: University of Rochester
Soumya Mitra: University of Rochester
C. Frank Bennett: Ionis Pharmaceuticals
Frank Rigo: Ionis Pharmaceuticals
Thomas H. Foster: University of Rochester
Thurman M. Wheeler: Massachusetts General Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07517-y

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