Accorsi Anthony, Kumar Ajay, Rhee Younghwa, Miller Alex, Girgenrath Mahasweta
Department of Health Sciences, Boston University, 635 Commonwealth Avenue, Boston, MA 02215, USA.
Pfizer Inc., 610 Main Street, Cambridge, MA 02319, USA.
Hum Mol Genet. 2016 Oct 24;25(21):4624–4634. doi: 10.1093/hmg/ddw291.
As the complexities of dystrophic pathology have been elucidated over the last few years, it has become increasingly clear that primary monogenetic defects result in multiple secondary pathologies capable of autonomously driving disease progression. Consequently, single-mode therapies fail to comprehensively ameliorate all aspects of pathology. Lama2-related muscular dystrophy (MDC1A) is a devastating congenital muscular dystrophy caused by mutations in the LAMA2 gene that results in multi-faceted secondary pathologies that include inflammation, fibrosis, apoptosis, and necrosis leading to severe muscle weakness and minimal postnatal growth. This study sought to implement a novel combinatorial treatment utilizing losartan, previously shown to ameliorate fibrosis and inflammation in conjunction with transgenic IGF-1 overexpression to improve postnatal growth. We found that dual-therapy rescued inflammation and fibrosis, improved weight gain, and led to remarkable restoration of muscle architecture and locomotory function in DyW mice (mouse model of MDC1A). We further showed using murine growth hormone that postnatal intervention with both therapies also yielded impressive amelioration of dystrophic pathology. Our results suggest for the first time that a combinatorial anti-fibrotic and pro-myogenic therapy could be the foundation of future therapies to a population of afflicted children in serious need.
在过去几年里，随着营养不良病理学的复杂性得以阐明，越来越清楚的是，原发性单基因缺陷会导致多种继发性病变，这些病变能够自主推动疾病进展。因此，单一模式疗法无法全面改善病理学的所有方面。与层粘连蛋白α2相关的肌营养不良症（MDC1A）是一种严重的先天性肌营养不良症，由LAMA2基因突变引起，会导致多方面的继发性病变，包括炎症、纤维化、细胞凋亡和坏死，进而导致严重的肌肉无力和出生后生长发育迟缓。本研究试图采用一种新的联合治疗方法，即使用之前已证明可改善纤维化和炎症的氯沙坦，并联合转基因IGF-1过表达来促进出生后的生长。我们发现，双重疗法可缓解炎症和纤维化，增加体重，并使DyW小鼠（MDC1A小鼠模型）的肌肉结构和运动功能得到显著恢复。我们进一步利用鼠生长激素表明，两种疗法在出生后进行干预也能显著改善营养不良病理学。我们的结果首次表明，抗纤维化和促肌生成联合疗法可能成为未来治疗急需帮助的患病儿童群体的基础。
