Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery

Yeon-Suk Yang, Jung-Min Kim, Jun Xie, Sachin Chaugule, Chujiao Lin, Hong Ma, Edward Hsiao, Jaehyoung Hong, Hyonho Chun, Eileen M. Shore, Frederick S. Kaplan, Guangping Gao () and Jae-Hyuck Shim ()
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Yeon-Suk Yang: UMass Chan Medical School
Jung-Min Kim: UMass Chan Medical School
Jun Xie: UMass Chan Medical School
Sachin Chaugule: UMass Chan Medical School
Chujiao Lin: UMass Chan Medical School
Hong Ma: UMass Chan Medical School
Edward Hsiao: University of California-San Francisco
Jaehyoung Hong: Korea Advanced Institute of Science and Technology
Hyonho Chun: Korea Advanced Institute of Science and Technology
Eileen M. Shore: The Perelman School of Medicine at the University of Pennsylvania
Frederick S. Kaplan: The Perelman School of Medicine at the University of Pennsylvania
Guangping Gao: UMass Chan Medical School
Jae-Hyuck Shim: UMass Chan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Heterotopic ossification is the most disabling feature of fibrodysplasia ossificans progressiva, an ultra-rare genetic disorder for which there is currently no prevention or treatment. Most patients with this disease harbor a heterozygous activating mutation (c.617 G > A;p.R206H) in ACVR1. Here, we identify recombinant AAV9 as the most effective serotype for transduction of the major cells-of-origin of heterotopic ossification. We use AAV9 delivery for gene replacement by expression of codon-optimized human ACVR1, ACVR1R206H allele-specific silencing by AAV-compatible artificial miRNA and a combination of gene replacement and silencing. In mouse skeletal cells harboring a conditional knock-in allele of human mutant ACVR1 and in patient-derived induced pluripotent stem cells, AAV gene therapy ablated aberrant Activin A signaling and chondrogenic and osteogenic differentiation. In Acvr1(R206H) knock-in mice treated locally in early adulthood or systemically at birth, trauma-induced endochondral bone formation was markedly reduced, while inflammation and fibroproliferative responses remained largely intact in the injured muscle. Remarkably, spontaneous heterotopic ossification also substantially decreased in in Acvr1(R206H) knock-in mice treated systemically at birth or in early adulthood. Collectively, we develop promising gene therapeutics that can prevent disabling heterotopic ossification in mice, supporting clinical translation to patients with fibrodysplasia ossificans progressiva.

Date: 2022
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DOI: 10.1038/s41467-022-33956-9

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