This proposal addresses a matter of key importance for drug discovery: development of biomarkers that monitor drug effects in vivo. We focus on myotonic dystrophy (dystrophia myotonica) type 1 (DM1), the most common muscular dystrophy in adults. DM1 is a dominantly inherited disorder caused by expression of DM protein kinase (DMPK) transcripts that contain an expanded CUG repeat (CUGexp). A well-understood consequence of CUGexp RNA expression includes mis-regulation of alternative splicing ("RNA toxicity"). In DM1 mouse models, therapeutic antisense oligonucleotides induce correction of alternative splicing patterns through modulation of CUGexp RNA toxicity. We, and others, are screening for endogenous biomarkers of disease activity and drug effect. In this proposal, we adopt an alternative approach by engineering novel biomarkers that enable non-invasive or minimally invasive detection, within minutes, of whether new treatments are having their intended effect. Our overall strategy involves the use of non-invasive fluorescence measurements to identify in vivo correction of alternative splicing in live DM1 mouse models. Efforts will include development of a high throughput in vivo screening assay to identify candidate drugs. The ultimate goal is to develop novel biomarkers that enable rapid identification of drug effects, demonstrate minimal toxicity, speed throughput of drug discovery, and, with modification, will translate to patients. Our approach will have broad application for genetic disorders beyond DM1 that are candidates for RNA modulation therapies.
Myotonic dystrophy is the most common muscular dystrophy in adults and the most prevalent overall. There is no cure. The purpose of this proposal is to develop novel strategies that will accelerate discovery of effective treatments.