Targeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy

Steven S Welc,James G Tidball,Ying Wang,Michelle Wehling-Henricks,Julian Ramos,Ivan Flores,Carmen Bertoni

doi:10.1038/s41467-019-10614-1

Steven S Welc, James G Tidball + Show 5 more

Open Access

https://doi.org/10.1038/s41467-019-10614-1

Copy DOI

Abstract

Many potentially therapeutic molecules have been identified for treating Duchenne muscular dystrophy. However, targeting those molecules only to sites of active pathology is an obstacle to their clinical use. Because dystrophic muscles become extensively inflamed, we tested whether expressing a therapeutic transgene in leukocyte progenitors that invade muscle would provide selective, timely delivery to diseased muscle. We designed a transgene in which leukemia inhibitory factor (LIF) is under control of a leukocyte-specific promoter and transplanted transgenic cells into dystrophic mice. Transplantation diminishes pathology, reduces Th2 cytokines in muscle and biases macrophages away from a CD163+/CD206+ phenotype that promotes fibrosis. Transgenic cells also abrogate TGFβ signaling, reduce fibro/adipogenic progenitor cells and reduce fibrogenesis of muscle cells. These findings indicate that leukocytes expressing a LIF transgene reduce fibrosis by suppressing type 2 immunity and highlight a novel application by which immune cells can be genetically modified as potential therapeutics to treat muscle disease.

Highlights

Many potentially therapeutic molecules have been identified for treating Duchenne muscular dystrophy
The introduction of therapeutic transgenes that are expressed at elevated levels in activated macrophages or other immune cells could provide a strategy for intrinsically-regulated targeting of therapeutic molecules to dystrophic muscles at the time of active pathology and at levels that were commensurate with the extent of pathology
We test whether transplantation of bone marrow cells (BMCs) into which we have introduced a leukemia inhibitory factor (LIF) transgene controlled by the human CD11b promoter reduces the pathology of mdx dystrophy

Summary

Introduction

Many potentially therapeutic molecules have been identified for treating Duchenne muscular dystrophy. The introduction of therapeutic transgenes that are expressed at elevated levels in activated macrophages or other immune cells could provide a strategy for intrinsically-regulated targeting of therapeutic molecules to dystrophic muscles at the time of active pathology and at levels that were commensurate with the extent of pathology. In this investigation, we test whether transplantation of bone marrow cells (BMCs) into which we have introduced a leukemia inhibitory factor (LIF) transgene controlled by the human CD11b promoter reduces the pathology of mdx dystrophy. The findings indicate that inflammatory cells can be exploited as natural vectors to deliver therapeutic transgenes for the treatment of chronic diseases in which there is a significant inflammatory component

Methods

Results

Conclusion