Mesoangioblast delivery of miniagrin ameliorates murine model of merosin-deficient congenital muscular dystrophy type 1A.

Teuta Domi,Rossana Tonlorenzi,Alessandro Ambrosi,Stefano Carlo Previtali,Alessia Capotondo,Daniele Velardo,Yuko Miyagoe-Suzuki,Stefano Amadio,Shin’Ichi Takeda,Alessandra Biffi,Markus A Ruegg,Emanuela Porrello

doi:10.1186/s13395-015-0055-5

Abstract

BackgroundMerosin-deficient congenital muscular dystrophy type-1A (MDC1A) is characterized by progressive muscular dystrophy and dysmyelinating neuropathy caused by mutations of the α2 chain of laminin-211, the predominant laminin isoform of muscles and nerves. MDC1A has no available treatment so far, although preclinical studies showed amelioration of the disease by the overexpression of miniagrin (MAG). MAG reconnects orphan laminin-211 receptors to other laminin isoforms available in the extracellular matrix of MDC1A mice.MethodsMesoangioblasts (MABs) are vessel-associated progenitors that can form the skeletal muscle and have been shown to restore defective protein levels and motor skills in animal models of muscular dystrophies. As gene therapy in humans still presents challenging technical issues and limitations, we engineered MABs to overexpress MAG to treat MDC1A mouse models, thus combining cell to gene therapy.ResultsMABs synthesize and secrete only negligible amount of laminin-211 either in vitro or in vivo. MABs engineered to deliver MAG and injected in muscles of MDC1A mice showed amelioration of muscle histology, increased expression of laminin receptors in muscle, and attenuated deterioration of motor performances. MABs did not enter the peripheral nerves, thus did not affect the associated peripheral neuropathy.ConclusionsOur study demonstrates the potential efficacy of combining cell with gene therapy to treat MDC1A.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-015-0055-5) contains supplementary material, which is available to authorized users.

Highlights

Merosin-deficient congenital muscular dystrophy type-1A (MDC1A) is characterized by progressive muscular dystrophy and dysmyelinating neuropathy caused by mutations of the α2 chain of laminin-211, the predominant laminin isoform of muscles and nerves
We evaluated if MABs can synthesize other laminin isoforms expressed in the muscle and nerve and observed in merosin-deficient congenital muscular dystrophy type 1A (MDC1A) mutants [3, 4, 19, 23]: we detected by immunohistochemistry laminin chains α4 and α5 but not α1 (Fig. 2a–c)
Staining for α7 integrin was reduced in dy2J mice as compared to wild type (Wt) and moderately increased in dy2J mice treated with MABs + mouse MAG (mMAG). d Western blot analysis confirmed the decrease of α7 integrin in dy2J, whereas it was more similar to Wt in dy2J mice treated with MABs or MABs + mMAG; differences were not significant. e Western blot analysis of α5 integrin showed a significant increase in all the dy2J

Summary

Introduction

Merosin-deficient congenital muscular dystrophy type-1A (MDC1A) is characterized by progressive muscular dystrophy and dysmyelinating neuropathy caused by mutations of the α2 chain of laminin-211, the predominant laminin isoform of muscles and nerves. Merosin-deficient congenital muscular dystrophy type 1A (MDC1A; OMIM #607855) is a severe and progressive muscle-wasting neuromuscular disease that frequently leads to death in early childhood. Mutations result in loss of interaction with laminin-211 receptors expressed by striated muscle and Schwann cells, primarily integrin α7β1, α6β1, and dystroglycan [4,5,6], leading to progressive tissue degeneration and to muscular dystrophy and neuropathy [7,8,9,10,11,12,13].

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