Proteomics-based evaluation of AAV dystrophin gene therapy outcomes in mdx skeletal muscle
Erynn E. Johnson, Theodore R. Reyes, Jeffrey S. Chamberlain, James M. Ervasti, Hichem Tasfaout
TL;DR
This study uses proteomics to assess how well different AAV-based dystrophin therapies work in a mouse model of Duchenne muscular dystrophy.
Contribution
A novel proteomics-based method is introduced to evaluate dystrophin replacement therapies in dystrophic mice.
Findings
Proteomics reveals changes in protein expression profiles in dystrophic and treated mouse muscles.
Successful dystrophin expression restores muscle homeostasis to varying degrees.
Potential biomarkers for evaluating dystrophin therapy effectiveness are identified.
Abstract
Duchenne muscular dystrophy (DMD) is a fatal genetic muscle-wasting disease characterized by loss of dystrophin protein. Therapeutic attempts to restore a functional copy of dystrophin to striated muscle are under active development, and many utilize adeno-associated viral (AAV) vectors. However, the limited cargo capacity of AAVs precludes delivery of full-length dystrophin, a 427 kDa protein, to target tissues. Recently, we developed a method to express large dystrophin constructs using the protein trans-splicing mechanism mediated by split inteins and myotropic AAV vectors. The efficacy of this approach to restore muscle function in mdx4cv mice was previously assessed using histology, dystrophin immunolabeling, and Western blotting. Here, we expand our molecular characterization of dystrophin constructs with variable lengths using a mass spectrometry–based proteomics approach,…
Genes, proteins, chemicals, diseases, species, mutations and cell lines named across the full text — each resolved to its canonical identifier and authoritative record.
Click any figure to enlarge with its caption.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10Peer Reviews
No public reviews on file for this paper yet. If you reviewed it on a platform where reviews are public (OpenReview, ICLR, NeurIPS, ICML), you can paste yours below so the community can read it here.
Videos
No videos yet. Explain this paper in a talk, walkthrough, or lecture? Add one.
Taxonomy
TopicsMuscle Physiology and Disorders · CRISPR and Genetic Engineering · GDF15 and Related Biomarkers