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AAV 介导的骨化性纤维发育不良中激活素 A-ACVR1 信号靶向治疗。

AAV-Mediated Targeting of the Activin A-ACVR1 Signaling in Fibrodysplasia Ossificans Progressiva.

机构信息

Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.

Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.

出版信息

Biomolecules. 2023 Sep 8;13(9):1364. doi: 10.3390/biom13091364.

DOI:10.3390/biom13091364
PMID:37759764
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10526456/
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 () 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) and artificial miRNAs targeting Activin A and its receptor ACVR1 ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of 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 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.

摘要

进行性骨化性纤维发育不良（FOP）是一种超罕见的遗传疾病，其特征是在骨骼外部位发生进行性致残性异位骨化（HO）。在这里，我们开发了基于腺相关病毒（AAV）的基因治疗方法，该方法可抑制携带人类 （）杂合子等位基因的 FOP 小鼠的创伤诱导性 HO，同时限制在非骨骼器官（如大脑、心脏、肺、肝和肾）中的表达。携带密码子优化的人 ACVR1（ACVR1）和靶向激活素 A 及其受体 ACVR1 的人工 microRNA 的 AAV 基因治疗消除了 BMP-Smad1/5 信号的异常激活和 骨骼祖细胞的成骨分化。将 AAV 基因治疗递送至骨骼肌中的 HO 发生细胞，可导致 FOP 小鼠的软骨内骨形成显著减少。由于富含肝脏的 miR-122 介导的抑制作用，这些小鼠在主要的 AAV 靶向器官肝脏中的表达很少或没有。因此，AAV 基因治疗是一种很有前途的治疗策略，可以探索抑制 FOP 中的 HO。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/4640bf18779b/biomolecules-13-01364-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/78f0012ef786/biomolecules-13-01364-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/5963cadf4b8d/biomolecules-13-01364-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/ae1d4330afce/biomolecules-13-01364-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/190e7e4548d6/biomolecules-13-01364-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/8bd5a5cdf403/biomolecules-13-01364-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/4640bf18779b/biomolecules-13-01364-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/78f0012ef786/biomolecules-13-01364-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/5963cadf4b8d/biomolecules-13-01364-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/ae1d4330afce/biomolecules-13-01364-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/190e7e4548d6/biomolecules-13-01364-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/8bd5a5cdf403/biomolecules-13-01364-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d90/10526456/4640bf18779b/biomolecules-13-01364-g006.jpg

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Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva.

J Zhejiang Univ Sci B. 2025-4-23

[2]
Fibrodysplasia ossificans progressiva: genetic and clinical characterization in a cohort of Polish patients and review of potential therapies.

J Appl Genet. 2025-4-12

[3]
FOP: From Biomolecules to Hope.

Biomolecules. 2025-2-24

[4]
The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model.

Pharmaceutics. 2024-11-25

[5]
The role of miRNAs as biomarkers in heterotopic ossification.

EFORT Open Rev. 2024-12-2

[6]
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Biomolecules. 2024-8-15

[7]
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[8]
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Biomolecules. 2024-3-16

[9]
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[10]
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本文引用的文献

[1]
FDA approves first gene therapy for Duchenne muscular dystrophy, despite internal objections.

Nat Rev Drug Discov. 2023-8

[2]
Researchers welcome $3.5-million haemophilia gene therapy - but questions remain.

Nature. 2022-12

[3]
Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery.

Nat Commun. 2022-10-19

[4]
Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors.

Nat Biomed Eng. 2022-11

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Adenine Base Editing with a Single Adeno-Associated Virus Vector.

GEN Biotechnol. 2022-6-1

[6]
Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification.

J Bone Miner Res. 2022-11

[7]
Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles.

Hum Gene Ther. 2022-8

[8]
Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization.

Orphanet J Rare Dis. 2021-8-5

[9]
MyD88 Is Not Required for Muscle Injury-Induced Endochondral Heterotopic Ossification in a Mouse Model of Fibrodysplasia Ossificans Progressiva.

Biomedicines. 2021-6-1

[10]
Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy.

JAMA Neurol. 2021-7-1

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