ABSTRACT
Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene, accompanied by aberrant extracellular matrix synthesis and muscle damage. ADAMTS1 metalloproteinase was reported increased in dystrophin-deficient mdx mouse. The aim of this study was to explore the role of ADAMTS1 in muscle function, fibrosis and damage, and respiratory function of mdx mice. 102 DMD patients and their mothers were included in this study. Multiplex ligation dependent probe amplification (MLPA) assay and Next-generation sequencing (NGS) were adopted to do genetic diagnosis. Dystrophin-deficient mdx mice were treated with anti-ADAMTS1 antibody (anti-ADAMTS1) for three weeks. The results showed that ADAMTS1 was increased in gastrocnemius muscle of mdx mice and serum of DMD patients. Anti-ADAMTS1 treatment increased Versican transcription but suppressed versican protein expression. Besides, we found anti-ADAMTS1 improved muscle strength, diaphragm and extensor digitorum longus muscles functions in mdx mice. Meanwhile, muscle fibrosis and damage were attenuated in anti-ADAMTS1 treated dystrophic mice. In summary, anti-ADAMTS1 antibody relieved muscle dysfunction and fibrosis in dystrophic mice. It is suggested that ADAMTS1 is a potential target for developing new biological therapies for DMD.
Subject(s)
ADAMTS1 Protein/antagonists & inhibitors , Antibodies, Monoclonal/therapeutic use , Muscle, Skeletal/drug effects , Muscular Dystrophy, Duchenne/therapy , ADAMTS1 Protein/genetics , ADAMTS1 Protein/immunology , ADAMTS1 Protein/metabolism , Animals , Disease Models, Animal , Dystrophin/genetics , Fibrosis/therapy , Humans , Male , Mice , Mice, Inbred mdx , Muscle Proteins/metabolism , Muscle Strength/immunology , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Dystrophy, Duchenne/genetics , RNA, Messenger/metabolism , Versicans/immunologyABSTRACT
Lentiviral vectors (LVs) transduce quiescent cells and provide stable integration to maintain transgene expression. Several approaches have been adopted to optimize LV safety profiles. Similarly, LV targeting has been tailored through strategies including the modification of envelope components, the use of specific regulatory elements, and the selection of appropriate administration routes. Models of aortic disease based on a single injection of pleiotropic LVs have been developed that efficiently transduce the three aorta layers in wild type mice. This approach allows the dissection of pathways involved in aortic aneurysm formation and the identification of targets for gene therapy in aortic diseases. LVs provide a fast, efficient, and affordable alternative to genetically modified mice to study disease mechanisms and develop therapeutic tools.
