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