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Gene Ther 2021 Feb 2. Epub 2021 Feb 2.

Friedrich Baur Institute, Department of Neurology, LMU Munich, Munich, Germany.

Mutations in Dystrophin, one of the largest proteins in the mammalian body, are causative for a severe form of muscle disease, Duchenne Muscular Dystrophy (DMD), affecting not only skeletal muscle, but also the heart. In particular, exons 45-52 constitute a hotspot for DMD mutations. A variety of molecular therapies have been developed, comprising vectors encoding micro- and minidystrophins as well as utrophin, a protein with partially overlapping functions. Read More

Hum Mol Genet 2021 Jan 11. Epub 2021 Jan 11.

Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA.

The dystrophin-glycoprotein complex (DGC) is a membrane adhesion complex that provides structural stability at the sarcolemma by linking the myocyte's internal cytoskeleton and external extracellular matrix. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to the loss of the DGC at the sarcolemma, resulting in sarcolemmal instability and progressive muscle damage. Utrophin, an autosomal homologue of dystrophin, is upregulated in dystrophic muscle and partially compensates for loss of dystrophin in muscle from patients with DMD. Read More

Aging (Albany NY) 2020 12 23;12(24):24853-24871. Epub 2020 Dec 23.

Steadman Philippon Research Institute, Center for Regenerative Sports Medicine, Vail, CO 81657, USA.

Duchenne Muscular Dystrophy (DMD) patients often suffer from both muscle wasting and osteoporosis. Our previous studies have revealed reduced regeneration potential in skeletal muscle and bone, concomitant with ectopic calcification of soft tissues in double knockout (, ; utrophin-/-) mice, a severe murine model for DMD. We found significant involvement of RhoA/ROCK (Rho-Associated Protein Kinase) signaling in mediating ectopic calcification of muscles in mice. Read More

ACS Med Chem Lett 2020 Dec 4;11(12):2421-2427. Epub 2020 Nov 4.

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K.

Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. Read More

Sci Rep 2020 12 9;10(1):21492. Epub 2020 Dec 9.

Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, 755 Clinical Research Building, Philadelphia, PA, 19104, USA.

Upregulation of utrophin, a dystrophin related protein, is considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Utrophin expression is repressed at the post-transcriptional level by a set of miRNAs, among which let-7c is evolutionarily highly conserved. We designed PMO-based SBOs complementary to the let-7c binding site in UTRN 3'UTR, with the goal of inhibiting let-7c interaction with UTRN mRNA and thus upregulating utrophin. Read More