| First Author | Yang YS | Year | 2023 |
| Journal | Biomolecules | Volume | 13 |
| Issue | 9 | PubMed ID | 37759764 |
| Mgi Jnum | J:357750 | Mgi Id | MGI:7537522 |
| Doi | 10.3390/biom13091364 | Citation | Yang YS, et al. (2023) AAV-Mediated Targeting of the Activin A-ACVR1(R206H) Signaling in Fibrodysplasia Ossificans Progressiva. Biomolecules 13(9) |
| abstractText | Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human ACVR1(R206H) (Acvr1(R206H/+)) while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1(opt)) and artificial miRNAs targeting Activin A and its receptor ACVR1(R206H) ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of Acvr1(R206H/+) skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in Acvr1(R206H/+) mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP. |
