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Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery
Nature Communications ( IF 14.7 ) Pub Date : 2022-10-19 , DOI: 10.1038/s41467-022-33956-9
Yeon-Suk Yang 1 , Jung-Min Kim 1 , Jun Xie 2, 3, 4 , Sachin Chaugule 1 , Chujiao Lin 1 , Hong Ma 2, 3, 4 , Edward Hsiao 5 , Jaehyoung Hong 6 , Hyonho Chun 6 , Eileen M Shore 7, 8, 9 , Frederick S Kaplan 7, 9, 10 , Guangping Gao 2, 3, 4, 11 , Jae-Hyuck Shim 1, 2, 11
Affiliation  

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.



中文翻译:


使用 AAV 基因递送抑制进行性骨化性纤维发育不良的异位骨化



异位骨化是进行性骨化性纤维发育不良最严重的特征,这是一种极其罕见的遗传性疾病,目前尚无预防或治疗方法。大多数患有这种疾病的患者在 ACVR1 中存在杂合激活突变 (c.617 G > A;p.R206H)。在这里,我们确定重组 AAV9 是异位骨化主要细胞来源转导最有效的血清型。我们使用 AAV9 递送通过表达密码子优化的人类 ACVR1 进行基因替换,通过 AAV 兼容的人工 miRNA 进行 ACVR1R206H 等位基因特异性沉默,以及基因替换和沉默的组合。在含有人类突变体 ACVR1 条件敲入等位基因的小鼠骨骼细胞和患者来源的诱导多能干细胞中,AAV 基因治疗消除了异常的激活素 A 信号传导以及软骨形成和成骨分化。在成年早期局部治疗或出生时全身治疗的 Acvr1(R206H) 敲入小鼠中,创伤诱导的软骨内骨形成显着减少,而受伤肌肉中的炎症和纤维增殖反应基本保持完整。值得注意的是,在出生时或成年早期接受系统治疗的 Acvr1(R206H) 敲入小鼠中,自发异位骨化也显着减少。总的来说,我们开发了有前途的基因疗法,可以预防小鼠的致残异位骨化,支持临床转化为进行性骨化性纤维发育不良患者。

更新日期:2022-10-19
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