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.

中文翻译：

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非侵入性监测替代剪接结果，以识别1型强直性肌营养不良的候选疗法。

在药物开发过程中，组织样本可作为疾病活动和药效学反应的指标。可靠的药物靶标非侵入性测量方法将有助于确定有前途的新疗法。在这里，我们开发并验证了一种强直性营养不良型1（DM1）的新型双转基因小鼠模型，其中DsRed或GFP的表达是通过在DM1中被错误调节的上游小基因的选择性剪接来确定的。使用新型的体内荧光光谱系统，我们显示DsRed / GFP比值的定量提供了活体小鼠肌肉组织中剪接结果的准确估计，这比常规荧光成像技术的通量提高了近一倍。