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Targeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy
- Source :
- Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019), Nature Communications, Nature communications, vol 10, iss 1
- Publication Year :
- 2019
- Publisher :
- Nature Portfolio, 2019.
-
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.<br />A number of therapeutic agents aimed at reducing pathology in Duchenne muscular dystrophy have been developed, but may have off-target effects when delivered systemically. Here, the authors express the therapeutic LIF transgene in leukocytes, and show this results in targeting to inflamed dystrophic muscle and reduced fibrosis by suppressing type 2 immunity.
- Subjects :
- 0301 basic medicine
Male
Duchenne muscular dystrophy
General Physics and Astronomy
Skeletal muscle
Diseases
02 engineering and technology
Leukemia Inhibitory Factor
Mice
Random Allocation
Myocyte
Muscular Dystrophy
Transgenes
Muscular dystrophy
lcsh:Science
Pediatric
Multidisciplinary
Skeletal
Neuromuscular disease
021001 nanoscience & nanotechnology
3. Good health
Specific Pathogen-Free Organisms
5.1 Pharmaceuticals
Muscle
Stem Cell Research - Nonembryonic - Non-Human
Development of treatments and therapeutic interventions
0210 nano-technology
Biotechnology
Duchenne/ Becker Muscular Dystrophy
Transgene
Intellectual and Developmental Disabilities (IDD)
Science
Bone Marrow Cells
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
Immune system
Rare Diseases
medicine
Genetics
Animals
Progenitor cell
Muscle, Skeletal
Inflammation
5.2 Cellular and gene therapies
business.industry
Animal
Inbred mdx
General Chemistry
Genetic Therapy
Muscular Dystrophy, Animal
medicine.disease
Stem Cell Research
Brain Disorders
Transplantation
030104 developmental biology
Gene Expression Regulation
Musculoskeletal
Cancer research
Mice, Inbred mdx
lcsh:Q
business
Leukemia inhibitory factor
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....d4537661a9358cce00b29d730758f523