Quantifying anti-DUX4 therapy for facioscapulohumeral muscular dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited skeletal myopathy with no cure. Expression of the myotoxic transcription factor double homeobox 4 (DUX4) is believed to underlie FSHD pathogenesis and many proposed therapies target DUX4 generation or function. Which of these therapies will be the most effective is unclear. Here, by constructing a Markov-chain-based mathematical model of DUX4-mediated myotoxity in FSHD, we interrogate various anti-DUX4 FSHD therapeutic strategies. We derive an analytical function for myonuclear life expectancy in terms of the parameters of DUX4 expression and function. In a biologically relevant parameter regime, therapeutically decreasing the DUX4 protein diffusion rate is, surprisingly, predicted to be more effective at increasing myonuclear life expectancy than reducing the rate of myonuclear apoptosis caused by the expression of DUX4-target genes. We find that targeting elements of DUX4 transcription/translation, such as mRNA stability via siRNA therapy, has a limited predicted impact on DUX4-meditated toxicity when performed in isolation. However, our model predicts a super-additive effect from combining transcription/translation targeting strategies with approaches that minimise DUX4 diffusion-mediated import into neighbouring myonuclei. Importantly, we provide a computational tool to test and inform therapeutic designs, enabling pre-clinical screening of FSHD treatment approaches.