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

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.

Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy

“…However, due to the genetic heterogeneity underlying hypoglycosylation in dystroglycanopathy, alternative strategies have been proposed that bypass the need for restoring Dystroglycan glycosylation altogether (Gumlaw et al, 2020). In sum, understanding Dystroglycan’s roles in brain development will allow for more effective gene therapies aimed at restoring cognitive function in human patients with dystroglycanopathy.…”

Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods

“…In fact, compounds that enhance matriglycan modification have been identified [ 77 , 78 ], and these, including compounds that enhance LARGE1 gene expression, are interesting therapeutic candidates. In addition, instead of targeting matriglycan, antibody therapy that connects cell membrane and basement membrane using a bivalent antibody against laminin and DG has been proposed [ 79 ].…”

New Opportunities in Glycan Engineering for Therapeutic Proteins

“…This “functional decoration” is part of a transmembrane link of the dystrophin-associated glycoprotein complex (DGC) between the extracellular matrix such as laminins, intracellular dystrophin, and the cytoskeleton, for providing resistance to sheared stresses during muscle activity. A bispecific antibody fusion could be generated, serving as a molecular linker to ameliorate sarcolemmal fragility for improving muscle function [ 76 ]. A host of enzymes such as the bifunctional glycosyltransferase LARGE are required for synthesizing α-DG mannosylation [ 16 , 77 ].…”

“…The local injection of recombinant α-dystroglycan (α-DG) produced by HEK293 co-transfected with LARGE rescues muscle activity in α-DG knockout or Large myd -mutant mice [ 78 ]. When the matriglycan-glycosylated α-DG is injected systemically, very little change is noted in muscle tissues, presumably due to the rapid clearance by the MR or ASGPR [ 76 ]. This result indicates that O-mannosylation of α-DG does interact with the extracellular matrix for therapeutic remedy but has issues of bioavailability in circulation.…”