NEW THERAPEUTIC APPROACHES AND THEIR READOUT

Currently there is no cure for muscular dystrophies but recently but promising treatments have emerged, highlighting the need of robust biomarkers. Several biomarkers have been proposed but none of them can monitor drug response longitudinally in a dose-dependent fashion. We recently demonstrated that in an atrophic muscle process, including muscular dystrophies, the myostatin pathway is intrinsically down-regulated to counter balance muscle wasting. This process was reversible in MTM1-deficient myotubular myopathy upon gene transfer leading to reactivation of the myostatin pathway. Here we show that components of the myostatin pathway are robust and reliable circulating biomarkers of drug efficacy in a gene therapy approach for dystrophin deficiency. Using an AAV8-microdystrophin vector in the GRMD dog model of Duchenne muscular dystrophy we demonstrate that the intrinsic loss of myostatin production in GRMD muscle can be partially corrected by AAV8-microdystrophin transfer in a dose-dependent manner. Importantly, and in agreement with the partial rescue provided by a micro-gene transfer approach, circulating myostatin levels in treated GRMD never reached WT levels. Two-year follow-up further demonstrated a decrease of circulating myostatin levels after high-dose treatment later in the disease course. Myostatin levels are thus the first quantifyable biomarker allowing for the non-invasive monitoring of treatment efficacy by providing a measure, which can determine the overall degree of the gene therapy efficacy as well as a longitudinal monitoring tool to follow eventual decrease of the therapeutic effect. This biomarker may therefore be also useful in future to judge the effect of combined therapy approaches non-invasively. Because circulating myostatin levels represent the product of general muscle health and activity we predict that myostatin pathway monitoring can be used to judge therapy efficacy in a wide range of neuromuscular diseases, which are associated with muscle wasting.