Engineered muscle tissues with enhanced maturation enable the identification of clinically relevant rAAV capsids
Lievre, C.; Robert, B.; Mainieri, G.; Jaulin, N.; Cotinat, M.; Mandrycky, C. J.; Mack, D. L.; Adjali, O.; Le Guiner, C.; Fraysse, B.; Dupont, J.-B.
Show abstract
Developing in vitro models that recapitulate both the structure and function of native human tissues is crucial for a better understanding of pathophysiology and for improving the reliability of preclinical studies. Here, we demonstrate that engineered muscle tissues derived from human pluripotent stem cells can serve as an in vitro platform for gene therapy. Recombinant vectors derived from the adeno-associated virus transduce engineered muscle tissues with high efficiency and in a dose-dependent manner, allowing long term assessment of transgene expression in a human cellular context. We next used this model to conduct a comparative analysis of 8 natural AAV capsids and showed that their relative efficiency depends on engineered muscle tissue maturation level. In more mature tissues subjected to uniaxial mechanical stretch, AAV9 performed better, which is reminiscent of its high clinical potential in patients with neuromuscular disorders. Finally, our model also confirmed the higher efficiency of artificial MyoAAV variants specifically developed to have an improved muscle transduction. Altogether, this work demonstrates the potential of human engineered muscle tissues in the preclinical testing of AAV vectors, paving the way for the development of personalized gene therapy platforms.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury 93%
- Screening of Chimeric GAA Variants in a Preclinical Study of Pompe Disease Results in Candidate Vector for Hematopoietic Stem Cell Gene Therapy 92%
- AAV-mediated gene augmentation therapy restores critical functions in mutant iPSC-derived PRPF31+/- cells. 92%
Similar papers in this journal
- Improving angiogenesis ameliorates the efficacy of ASO-based exon-skipping for the treatment of Duchenne muscular dystrophy 94%
- AAVone: A Cost-Effective, Single-Plasmid Solution for Efficient AAV Production with Reduced DNA Impurities 93%
- A Genome-wide CRISPR screen unveils the endosomal maturation protein WDR91 as a promoter of productive ASO activity in melanoma 92%
Similar papers in this journal
- Preclinical lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy corrects Pompe disease-related muscle and neurological manifestations 93%
- Thymidylate synthase disruption to limit cell proliferation in cell therapies 92%
- AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy 91%
Similar papers in this journal
Similar papers in this journal
- Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition 95%
- Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSCs-derived myogenic progenitor cells 94%
- Efficient transgenesis and homology-directed gene targeting in monolayers of primary human small intestinal and colonic epithelial stem cells 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.