小柯机器人

美国宾夕法尼亚州立大学Hansell H. Stedman研究团队发现，无免疫原性的抗肌萎缩蛋白相关蛋白基因疗法，可用于治疗动物模型中的肌营养不良症。2019年10月7日，国际知名学术期刊《自然—医学》在线发表了这一成果。

研究人员设计了一种密码子优化的合成转基因，其编码可通过腺相关病毒（AAV）载体递送的微型抗肌萎缩蛋白相关蛋白（µUtro）。研究人员发现µUtro是肌营养不良蛋白的一种功能强大的非免疫原性替代品，可防止大小动物模型中肌肉营养不良带来的最有害的组织学和生理学影响。对新生的肌营养不良蛋白缺乏症的mdx小鼠全身施用AAV-µUtro之后，在整个成年体重增长过程中，完全抑制了坏死和再生的组织学和生化指标。在肌营养不良蛋白缺陷型金毛寻回犬模型中，即使在最强壮的肌肉中，μUtro也无毒地防止了心肌坏死。在严格的免疫原性测试中，在基因缺失的德国短毛指示犬模型中，µUtro的局部表达没有产生细胞介导的免疫反应，这与针对类似构建的µDystrophin（µDystro）所产生的强烈T细胞反应不同。这些发现支持了一种模型，即抗肌萎缩蛋白相关蛋白衍生疗法可用于治疗临床肌营养不良蛋白缺乏症，并且在蛋白及其微型化的情况下具有良好的免疫学特征同时具有功能。

据悉，杜氏肌营养不良症（DMD）基因的关键产物是抗肌萎缩蛋白，它是一种棒状蛋白，可保护横纹肌细胞免受收缩诱导的损伤。肌营养不良蛋白相关的蛋白质（或卵磷脂）保留了肌营养不良蛋白的大部分结构和蛋白质结合元件。重要的是，DMD患者的正常胸腺表达应通过中枢免疫耐受来保护抗肌萎缩蛋白相关蛋白（也称为utrophin）。

附：英文原文

Title: Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models

Author: Yafeng Song, Leon Morales, Alock S. Malik, Andrew F. Mead, Christopher D. Greer, Marilyn A. Mitchell, Mihail T. Petrov, Leonard T. Su, Margaret E. Choi, Shira T. Rosenblum, Xiangping Lu, Daniel J. VanBelzen, Ranjith K. Krishnankutty, Frederick J. Balzer, Emanuele Loro, Robert French, Kathleen J. Propert, Shangzhen Zhou, Benjamin W. Kozyak, Peter P. Nghiem, Tejvir S. Khurana, Joe N. Kornegay, Hansell H. Stedman

Issue&Volume: 2019-10-07

Abstract: The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (Utro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that Utro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-Utro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, Utro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of Utro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed Dystrophin (Dystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization. A gene therapy vector expressing micro-utrophin provides functional replacement of lost dystrophin, and lacks the adverse immunogenicity associated with direct dystrophin therapy, in rodent and canine models of Duchenne muscular dystrophy.

DOI: 10.1038/s41591-019-0594-0

Source:https://www.nature.com/articles/s41591-019-0594-0

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex