Next Article in Journal
Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists
Next Article in Special Issue
How Activin A Became a Therapeutic Target in Fibrodysplasia Ossificans Progressiva
Previous Article in Journal
Advances of Osteosarcoma Models for Drug Discovery and Precision Medicine
Previous Article in Special Issue
Polypeptide Substrate Accessibility Hypothesis: Gain-of-Function R206H Mutation Allosterically Affects Activin Receptor-like Protein Kinase Activity
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomolecules
Volume 13
Issue 9
10.3390/biom13091364
biomolecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva

by
Yeon-Suk Yang
1,†,
Chujiao Lin
1,†,
Hong Ma
2,3,4,
Jun Xie
2,3,4,
Frederick S. Kaplan
5,6,7,
Guangping Gao
2,3,4,8,* and
Jae-Hyuck Shim
1,2,8,*
1
Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
2
Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
3
Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
4
Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
5
Department of Orthopaedic Surgery, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
6
Department of Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
7
The Center for Research in FOP and Related Disorders, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
8
Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomolecules 2023, 13(9), 1364; https://doi.org/10.3390/biom13091364
Submission received: 28 July 2023 / Revised: 6 September 2023 / Accepted: 6 September 2023 / Published: 8 September 2023
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)
Browse Figures
Review Reports Versions Notes

Abstract

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 ACVR1R206H (Acvr1R206H/+) 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 (ACVR1opt) and artificial miRNAs targeting Activin A and its receptor ACVR1R206H ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of Acvr1R206H/+ 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 Acvr1R206H/+ 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.
Keywords: fibrodysplasia ossificans progressiva; heterotopic ossificans; Activin A; ACVR1; AAV; gene therapy fibrodysplasia ossificans progressiva; heterotopic ossificans; Activin A; ACVR1; AAV; gene therapy

Share and Cite

MDPI and ACS Style

Yang, Y.-S.; Lin, C.; Ma, H.; Xie, J.; Kaplan, F.S.; Gao, G.; Shim, J.-H. AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva. Biomolecules 2023, 13, 1364. https://doi.org/10.3390/biom13091364

AMA Style

Yang Y-S, Lin C, Ma H, Xie J, Kaplan FS, Gao G, Shim J-H. AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva. Biomolecules. 2023; 13(9):1364. https://doi.org/10.3390/biom13091364

Chicago/Turabian Style

Yang, Yeon-Suk, Chujiao Lin, Hong Ma, Jun Xie, Frederick S. Kaplan, Guangping Gao, and Jae-Hyuck Shim. 2023. "AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva" Biomolecules 13, no. 9: 1364. https://doi.org/10.3390/biom13091364

APA Style

Yang, Y.-S., Lin, C., Ma, H., Xie, J., Kaplan, F. S., Gao, G., & Shim, J.-H. (2023). AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva. Biomolecules, 13(9), 1364. https://doi.org/10.3390/biom13091364

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop