Amelioration of laminin-α2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin

Abstract

Congenital muscular dystrophy (CMD) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. Most of the CMD cases are caused by genetic mutations of laminin-␣2, which is essential for the structural integrity of muscle extracellular matrix. Here, we report that somatic gene delivery of a structurally unrelated protein, a miniature version of agrin, functionally compensates for laminin-␣2 deficiency in the murine models of CMD. Adeno-associated virusmediated overexpression of miniagrin restored the structural integrity of myofiber basal lamina, inhibited interstitial fibrosis, and ameliorated dystrophic pathology. Furthermore, systemic gene delivery of miniagrin into multiple vital muscles significantly improved whole body growth and motility and quadrupled the lifespan (50% survival) of the dystrophic mice. Thus, our study demonstrated the efficacy of somatic gene therapy in a mouse model of CMD.adeno-associated virus ͉ integrity ͉ myofiber basal laming ͉ gene therapy

Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin Alpha2-deficient Skeletal Muscle

“…The Lama2 dy-W mouse model for MDC1A along with other Lama2-deficient strains have been widely used to study features of Lama2-deficient muscle pathology, including muscle apoptosis, necrosis, regeneration, and various molecular and pharmacological interventions that can affect these. Most studies have evaluated later stages of pathology in mice 3 to 4 weeks of age and beyond (Kuang et al 1998;Kuang et al 1999;Moll et al 2001;Girgenrath et al 2004;Bentzinger et al 2005;Dominov et al 2005;Li et al 2005;Qiao et al 2005;Gawlik et al 2006;van Lunteren et al 2006;Meinen et al 2007;Erb et al 2009;Girgenrath et al 2009). By 4 weeks of age in this model, significant muscle degeneration has occurred, apoptosis of regenerating fibers has led to poor regeneration, and fibrosis has become a prominent feature.…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…In dy W /dy W mice a "replacement therapy" using a mini-agrin (miniaturized form of agrin) resulted in a lesser muscle degeneration and in a decrease of mortality that is mediated through the linking of muscle basement membrane to the DGC, and not to integrin 107 . The first attempt of somatic gene therapy to treat mice with laminin alpha-2 deficiency was performed by Qiao et al 108 . They used adeno-associated viral vector for delivering miniagrin gene into dy W /dy W mice and obtained an improvement of the dystrophic pattern.…”

“…From 1994, knock-out mouse or spontaneous mutant mouse strains have been identified as animal models for MDC1A with total and partial deficiency [99][100][101][102][103][104][105] , and experimental therapeutic strategies have been attempted 102,103,[106][107][108][109][110][111][112][113][114][115][116] . In mice, Kuang et al 102,103 were successful in obtaining the expression of a human laminin alpha 2 chain transgene under the regulation of a muscle-specific creatine kinase promoter.…”

Suppression of tissue inhibitor of metalloproteinase-1 by recombinant adeno-associated viruses carrying siRNAs in hepatic stellate cells

“…These investigations provided much of the safety profile of the vector and experience in human applications, paving the way for subsequent administration to other disorders such as hemophilia (13,14), retinal diseases (15,16), muscular dystrophy (17,18), neurological diseases (19,20) or cancer (21,22). Our results suggest that AAV vectors also have the potential for the therapeutic delivery of siRNA.…”