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

Steven S. Welc, Ivan Flores, Michelle Wehling-Henricks, Julian Ramos, Ying Wang, Carmen Bertoni and James G. Tidball ()
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Steven S. Welc: University of California
Ivan Flores: University of California
Michelle Wehling-Henricks: University of California
Julian Ramos: University of California
Ying Wang: University of California
Carmen Bertoni: University of California
James G. Tidball: University of California

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10614-1

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