Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse Jonathon M. Tinsley1*, Rebecca J. Fairclough 2 , Richard Storer1, Fraser J. Wilkes1, Allyson C. Potter2, Sarah E. Squire2, Dave S. Powell2, Anna Cozzoli3, Roberta F. Capogrosso3, Adam Lambert1, Francis X. Wilson1, Stephen P. Wren1, Annamaria De Luca3, Kay E. Davies2* 1 Summit plc, Abingdon, United Kingdom, 2 MRC Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom, 3 Unit of Pharmacology, Department of Pharmaco-biology, University of Bari ‘‘A. Moro’’, Bari, Italy Abstract Background: Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fibers leading to the gradual depletion of skeletal muscle. There is significant evidence demonstrating that increasing levels of the dystrophin-related protein, utrophin, in mouse models results in sarcolemmal bound utrophin and prevents the muscular dystrophy pathology. The aim of this work was to develop a small molecule which increases the levels of utrophin in muscle and thus has therapeutic potential. Methodology and Principal Findings: We describe the in vivo activity of SMT C1100; the first orally bioavailable small molecule utrophin upregulator. Once-a-day daily-dosing with SMT C1100 reduces a number of the pathological effects of dystrophin deficiency. Treatment results in reduced pathology, better muscle physiology leading to an increase in overall strength, and an ability to resist fatigue after forced exercise; a surrogate for the six minute walk test currently recommended as the pivotal outcome measure in human trials for DMD. Conclusions and Significance: This study demonstrates proof-of-principle for the use of in vitro screening methods in allowing identification of pharmacological agents for utrophin transcriptional upregulation. The best compound identified, SMT C1100, demonstrated significant disease modifying effects in DMD models. Our data warrant the full evaluation of this compound in clinical trials in DMD patients. Citation: Tinsley JM, Fairclough RJ, Storer R, Wilkes FJ, Potter AC, et al. (2011) Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse. PLoS ONE 6(5): e19189. doi:10.1371/journal.pone.0019189 Editor: Paul Dent, Virginia Commonwealth University, United States of America Received February 17, 2011; Accepted March 22, 2011; Published May 6, 2011 Copyright: 2011 Tinsley et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Medical Research Council, Muscular Dystrophy Campaign, Muscular Dystrophy Association USA, Association Francaise contre les Myopathies, and Telethon Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: JMT, RS, FJW, AL, FXW, SPW are employed by Summit plc. KED is a shareholder of Summit plc. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: Jon.Tinsley@summitplc.com (JMT); kay.davies@dpag.ox.ac.uk (KED) Introduction Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive muscle wasting disease caused by mutations in the dystrophin gene (for review see [1]). Affected boys are ambulatory until about 12 years of age but often live into their twenties with recent improvements in respiratory support. Many boys show an abnormal ECG in the late stages of the diseases and cardiomy- opathy is also a general feature. The milder form of the disease known as Becker muscular dystrophy (BMD) is also characterized by cardiac defects despite BMD patients often being ambulant in their 50s and 60s. Thus, any therapy for the disease would need not only to target skeletal, but also cardiac muscle. Currently there is no effective treatment for DMD. Various strategies developed to alleviate the symptoms include steroid treatment, anti-inflammatory agents, and growth hormone and myostatin inhibitors (for review see [2]). More recently, genetic approaches have been tested in DMD patient trials. In particular, readthrough of stop codons has been attempted in the 10–15% of patients that have mutations resulting in premature stop codons resulting in dystrophin deficiency. An orally delivered small molecule, Ataluren, recently entered a phase IIb trial. The six minute walk distance test [3] (6MWD) was used as the primary efficacy endpoint as the ability to walk further after treatment is considered by the regulatory authorities as a major improvement in the quality of life for these patients. Unfortunately, after conclusion of the trial, no statistically significant increase in the distance travelled using the 6MWD was reported. Skipping of exon 51, which targets up to 13% of patients, represents the monoskipping therapy which would be applicable to the largest proportion of DMD patients. Antisense molecules, delivered either intravenously or sub-cutaneously, have shown some restoration of dystrophin to a variable degree in patients [4,5]. Next generation trials are planned with constructs which increase the efficiency of PLoS ONE | www.plosone.org 1 May 2011 | Volume 6 | Issue 5 | e19189