Gaedigk Roger, Law Douglas J, Fitzgerald-Gustafson Kathleen M, McNulty Steven G, Nsumu Ndona N, Modrcin Ann C, Rinaldi Robert J, Pinson David, Fowler Stephen C, Bilgen Mehmet, Burns Joanne, Hauschka Stephen D, White Robert A
Department of Medical Research, Children's Mercy Hospitals & Clinics, Pediatric Research Building 4th Floor, 2401 Gillham, Kansas City, MO 64108, USA.
Neuromuscul Disord. 2006 Mar;16(3):192-203. doi: 10.1016/j.nmd.2005.12.007. Epub 2006 Feb 17.
Duchenne muscular dystrophy is a progressive muscle disease characterized by increasing muscle weakness and death by the third decade. mdx mice exhibit the underlying muscle disease but appear physically normal with ordinary lifespans, possibly due to compensatory expression of utrophin. In contrast, double mutant mice (mdx/utrn(-/-)), deficient for both dystrophin and utrophin die by approximately 3 months and suffer from severe muscle weakness, growth retardation, and severe spinal curvature. The capacity of human retinal dystrophin (Dp260) to compensate for the missing 427 kDa muscle dystrophin was tested in mdx/utrn(-/-) mice. Functional outcomes were assessed by histology, EMG, MRI, mobility, weight and longevity. MCK-driven transgenic expression of Dp260 in mdx/utrn(-/-) mice converts their disease course from a severe, lethal muscular dystrophy to a viable, mild myopathic phenotype. This finding is relevant to the design of exon-skipping therapeutic strategies since Dp260 lacks dystrophin exons 1-29.
杜氏肌营养不良症是一种进行性肌肉疾病，其特征是肌肉无力逐渐加重，并在三十岁前死亡。mdx小鼠表现出潜在的肌肉疾病，但身体外观正常，寿命也正常，这可能是由于抗肌萎缩蛋白聚糖的代偿性表达。相比之下，抗肌萎缩蛋白和抗肌萎缩蛋白聚糖均缺失的双突变小鼠（mdx/utrn(-/-)）在大约3个月时死亡，并患有严重的肌肉无力、生长发育迟缓以及严重的脊柱侧弯。在mdx/utrn(-/-)小鼠中测试了人类视网膜抗肌萎缩蛋白（Dp260）补偿缺失的427 kDa肌肉抗肌萎缩蛋白的能力。通过组织学、肌电图、磁共振成像、活动能力、体重和寿命评估功能结果。在mdx/utrn(-/-)小鼠中，由肌酸激酶（MCK）驱动的Dp260转基因表达将它们的病程从严重的致死性肌营养不良转变为可存活的轻度肌病表型。这一发现与外显子跳跃治疗策略的设计相关，因为Dp260缺少抗肌萎缩蛋白的外显子1-29。
