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触发再生和应对细胞凋亡:一种联合方法治疗 1 型先天性肌营养不良症。

Triggering regeneration and tackling apoptosis: a combinatorial approach to treating congenital muscular dystrophy type 1 A.

机构信息

Department of Health Sciences, Boston University, 635 Commonwealth Avenue, Boston, MA 02215, USA.

出版信息

Hum Mol Genet. 2013 Nov 1;22(21):4306-17. doi: 10.1093/hmg/ddt280. Epub 2013 Jun 16.

Abstract

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder caused by mutations in the laminin-α2 gene (OMIM: 607855). Currently, no treatment other than palliative care exists for this disease. In our previous work, genetic interventions in the Lama2(Dy-w) mouse model for MDC1A demonstrated that limited regeneration and uncontrolled apoptosis are important drivers of this disease. However, targeting one of these disease drivers without addressing the other results in only partial rescue of the phenotype. The present study was designed to determine whether utilizing a combinatorial treatment approach can lead to a more profound amelioration of the disease pathology. To accomplish this task, we generated Bax-null Lama2(Dy-w)mice that overexpressed muscle-specific IGF-1 (Lama2(Dy-w)Bax(-/-)+IGF-1tg). Further to test the translational potential of IGF-1 administration in combination with Bax inhibition, we treated Lama2(Dy-w)Bax(-/-) mice postnatally with systemic recombinant human IGF-1 (IPLEX™). These two combinatorial treatments lead to similar, promising outcomes. In addition to increased body and muscle weights, both transgenic overexpression and systemic administration of IGF-1 combined with Bax-inhibition resulted in improved muscle phenotype and locomotory function that were nearly indistinguishable from wild-type mice. These results provide a fundamental proof of concept that justifies the use of a combination therapy as an effective treatment for MDC1A and highlights a compelling argument toward shifting the paradigm in treating multifaceted neuromuscular diseases.

摘要

先天性肌营养不良症 1A 型(MDC1A)是一种常染色体隐性遗传病,由层粘连蛋白-α2 基因突变引起(OMIM:607855)。目前,除了姑息治疗外,这种疾病还没有其他治疗方法。在我们之前的工作中,对 MDC1A 的 Lama2(Dy-w)小鼠模型的遗传干预表明,有限的再生和不受控制的细胞凋亡是该疾病的重要驱动因素。然而,仅针对这些疾病驱动因素之一而不解决另一个因素,只会导致表型的部分挽救。本研究旨在确定是否利用组合治疗方法可以更深入地改善疾病病理学。为了实现这一目标,我们生成了 Bax 缺失的 Lama2(Dy-w)小鼠,这些小鼠过表达肌肉特异性 IGF-1(Lama2(Dy-w)Bax(-/-)+IGF-1tg)。为了进一步测试 IGF-1 联合 Bax 抑制给药在治疗中的转化潜力,我们在 Lama2(Dy-w)Bax(-/-) 小鼠出生后用系统重组人 IGF-1(IPLEX™)进行治疗。这两种组合治疗方法带来了类似的、有希望的结果。除了增加体重和肌肉重量外,IGF-1 的转基因过表达和系统给药与 Bax 抑制相结合,导致肌肉表型和运动功能得到改善,几乎与野生型小鼠无法区分。这些结果提供了一个基本的概念验证,证明了联合治疗作为 MDC1A 有效治疗方法的使用合理性,并强调了在治疗多方面神经肌肉疾病方面转变范式的强烈理由。

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