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      biAb Mediated Restoration of the Linkage between Dystroglycan and Laminin-211 as a Therapeutic Approach for α-Dystroglycanopathies

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      Molecular Therapy
      American Society of Gene & Cell Therapy
      α-dystroglycanopathy, congenital muscular dystrophy, limb-girdle muscular dystrophy, laminin-211, bispecific antibody, dystrophin-associated glycoprotein complex, α-dystroglycan, β-dystroglycan, LARGEmyd-3J mice, surrogate molecular linker

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          Abstract

          Patients with α-dystroglycanopathies, a subgroup of rare congenital muscular dystrophies, present with a spectrum of clinical manifestations that includes muscular dystrophy as well as CNS and ocular abnormalities. Although patients with α-dystroglycanopathies are genetically heterogeneous, they share a common defect of aberrant post-translational glycosylation modification of the dystroglycan alpha-subunit, which renders it defective in binding to several extracellular ligands such as laminin-211 in skeletal muscles, agrin in neuromuscular junctions, neurexin in the CNS, and pikachurin in the eye, leading to various symptoms. The genetic heterogeneity associated with the development of α-dystroglycanopathies poses significant challenges to developing a generalized treatment to address the spectrum of genetic defects. Here, we propose the development of a bispecific antibody (biAb) that functions as a surrogate molecular linker to reconnect laminin-211 and the dystroglycan beta-subunit to ameliorate sarcolemmal fragility, a primary pathology in patients with α-dystroglycan-related muscular dystrophies. We show that the treatment of LARGE myd-3J mice, an α-dystroglycanopathy model, with the biAb improved muscle function and protected muscles from exercise-induced damage. These results demonstrate the viability of a biAb that binds to laminin-211 and dystroglycan simultaneously as a potential treatment for patients with α-dystroglycanopathy.

          Graphical Abstract

          Abstract

          Patients with α-dystroglycanopathies, a subgroup of rare congenital muscular dystrophies, share a common defect that lacks glycosylation of dystroglycan, resulting in defective binding to several extracellular ligands. Gumlaw and Sevigny et al. present a strategy for a therapeutic bispecific antibody that functions as a surrogate molecular linker to reconnect laminin-211 and the dystroglycan beta-subunit.

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          Most cited references44

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          Dystroglycan: from biosynthesis to pathogenesis of human disease.

          Alpha- and beta-dystroglycan constitute a membrane-spanning complex that connects the extracellular matrix to the cytoskeleton. Although a structural role for dystroglycan had been identified, biochemical and genetic discoveries have recently highlighted the significance of posttranslational processing for dystroglycan function. Glycosylation is the crucial modification that modulates the function of dystroglycan as a receptor for extracellular binding partners. It has become clear that perturbation of dystroglycan glycosylation is the central event in the pathogenesis of several complex disorders, and recent advances suggest that glycosylation could be modulated to ameliorate the pathological features. Our increased understanding of the mechanisms of interaction of dystroglycan with its ligands has become an essential tool in deciphering the biological processes related to the human diseases in which the proteins are implicated.
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            Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals.

            The 14 kb human Duchenne muscular dystrophy (DMD) cDNA corresponding to a complete representation of the fetal skeletal muscle transcript has been cloned. The DMD transcript is formed by at least 60 exons which have been mapped relative to various reference points within Xp21. The first half of the DMD transcript is formed by a minimum of 33 exons spanning nearly 1000 kb, and the remaining portion has at least 27 exons that may spread over a similar distance. The DNA isolated from 104 DMD boys was tested with the cDNA for detection of deletions and 53 patients exhibit deletion mutations. The majority of deletions are concentrated in a single genomic segment corresponding to only 2 kb of the transcript.
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              Engineering adeno-associated viruses for clinical gene therapy.

              Clinical gene therapy has been increasingly successful owing both to an enhanced molecular understanding of human disease and to progressively improving gene delivery technologies. Among these technologies, delivery vectors based on adeno-associated viruses (AAVs) have emerged as safe and effective and, in one recent case, have led to regulatory approval. Although shortcomings in viral vector properties will render extension of such successes to many other human diseases challenging, new approaches to engineer and improve AAV vectors and their genetic cargo are increasingly helping to overcome these barriers.
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                Author and article information

                Contributors
                Journal
                Mol Ther
                Mol. Ther
                Molecular Therapy
                American Society of Gene & Cell Therapy
                1525-0016
                1525-0024
                05 February 2020
                06 December 2019
                : 28
                : 2
                : 664-676
                Affiliations
                [1 ]Sanofi, Framingham, MA 01701-9322, USA
                Author notes
                []Corresponding author: Leila Sevigny, PhD, Sanofi, One The Mountain Rd., Framingham, MA 01701-9322, USA. leila.sevigny@ 123456sanofi.com
                [2]

                These authors contributed equally to this work.

                Article
                S1525-0016(19)30549-0
                10.1016/j.ymthe.2019.11.023
                7001080
                31843448
                3167da40-3832-47c8-94f6-fa48165fae0e
                © 2019 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 25 April 2019
                : 23 November 2019
                Categories
                Original Article

                Molecular medicine
                α-dystroglycanopathy,congenital muscular dystrophy,limb-girdle muscular dystrophy,laminin-211,bispecific antibody,dystrophin-associated glycoprotein complex,α-dystroglycan,β-dystroglycan,largemyd-3j mice,surrogate molecular linker

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