The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice.

Rylie M Hightower,S Armando Villalta,Andrea L Reid,Matthew S Alexander,Yosef Landesman,Savanna Gornisiewicz,Yimin Wang,Devin E Gibbs,Jenna M Kastenschmidt,Sharon Tamir,Hua Chang,Thomas Van Groen,Jeffrey J Widrick,Louis M Kunkel

doi:10.1016/j.ymthe.2019.08.016

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that is caused by the loss of functional dystrophin protein in cardiac and skeletal muscles. DMD patient muscles become weakened, leading to eventual myofiber breakdown and replacement with fibrotic and adipose tissues. Inflammation drives the pathogenic processes through releasing inflammatory cytokines and other factors that promote skeletal muscle degeneration and contributing to the loss of motor function. Selective inhibitors of nuclear export (SINEs) are a class of compounds that function by inhibiting the nuclear export protein exportin 1 (XPO1). The XPO1 protein is an important regulator of key inflammatory and neurological factors that drive inflammation and neurotoxicity in various neurological and neuromuscular diseases. Here, we demonstrate that SINE compound KPT-350 can ameliorate dystrophic-associated pathologies in the muscles of DMD models of zebrafish and mice. Thus, SINE compounds are a promising novel strategy for blocking dystrophic symptoms and could be used in combinatorial treatments for DMD.

Highlights

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the DYSTROPHIN gene resulting in the lack of production of functional dystrophin protein.[1,2] DMD affects approximately 1:5,000 live male births worldwide, making it the most common childhood form of muscular dystrophy
We evaluated the therapeutic ability of oral KPT-350 given to D2-mdx and control WT (DBA/2J) mice in the form of peanut butter pellets to ameliorate the dystrophic pathology and improve muscle function
KPT-350 Increases Macrophage Populations in D2-mdx Skeletal Our findings indicated that KPT-350 treatment improved muscle

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the DYSTROPHIN gene resulting in the lack of production of functional dystrophin protein.[1,2] DMD affects approximately 1:5,000 live male births worldwide, making it the most common childhood form of muscular dystrophy. There is no cure for DMD, and corticosteroids are the current primary standard-of-care treatment.[12,13] The functional preservation seen in patients in response to corticosteroid therapy is thought to be a result of their immunosuppressive properties, which reduces the detrimental fibrotic pathology associated with dystrophin deficiency.[14,15,16] Anti-fibrotic and anti-inflammatory compounds or biologics that target key drivers of inflammation in DMD, such as interleukin-6 (IL-6), transforming growth factor b (TGF-b), tumor necrosis factor alpha (TNF-a), the nuclear factor kB (NF-kB) signaling pathways, or regulatory T cells, have shown therapeutic efficacy in reducing dystrophic symptoms in dystrophin-deficient mice.[17,18] Regulatory T cells have been shown to block and/or ameliorate dystrophic symptoms in mouse and canine DMD models.[7,17,19,20,21,22,23,24,25,26]

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Results

Conclusion