Abstract：
LAMA2 deficiency, resulting from a defective or absent laminin α2 subunit, is a common cause of congenital muscular dystrophy. It is characterized by muscle weakness from myofiber degeneration and neuropathy from Schwann cell amyelination. Previously it was shown that transgenic muscle-specific expression of αLNNd, a laminin γ1-binding linker protein that enables polymerization in defective laminins, selectively ameliorates the muscle abnormality in mouse disease models. Here, adeno-associated virus was used to deliver linker mini-genes to dystrophic dy2J/dy2J mice for expression of αLNNd in muscle, or αLNNdΔG2\', a shortened linker, in muscle, nerve, and other tissues. Linker and laminin α2 levels were higher in αLNNdΔG2\'-treated mice. Both αLNNd- and αLNNdΔG2\'-treated mice exhibited increased forelimb grip strength. Further, αLNNdΔG2\'-treated mice achieved hind limb and all-limb grip strength levels approaching those of WT mice as well as ablation of hind limb paresis and contractures. This was accompanied by restoration of sciatic nerve axonal envelopment and myelination. Improvement of muscle histology was evident in the muscle-specific αLNNd-expressing mice but more extensive in the αLNNdΔG2\'-expressing mice. The results reveal that an αLN linker mini-gene, driven by a ubiquitous promoter, is superior to muscle-specific delivery because of its higher expression that extends to the peripheral nerve. These studies support a potentially novel approach of somatic gene therapy.
摘要：
LAMA2缺陷,由于层粘连蛋白α2亚基有缺陷或缺失，是先天性肌营养不良的常见原因。它的特征是肌纤维变性引起的肌肉无力和雪旺氏细胞淀粉化引起的神经病变。以前的研究表明，αLNNd的转基因肌肉特异性表达，层粘连蛋白γ1结合接头蛋白，能够在有缺陷的层粘连蛋白中聚合，选择性改善小鼠疾病模型中的肌肉异常。这里,腺相关病毒用于将接头小基因传递给营养不良的dy2J/dy2J小鼠，以在肌肉中表达αLNNd，或αLNNdΔG2'，一个缩短的接头，在肌肉中，神经,和其他组织。αLNNdΔG2'处理的小鼠中接头和层粘连蛋白α2水平较高。αLNNd-和αLNNdΔG2'处理的小鼠均表现出增加的前肢握力。Further,αLNNdΔG2'处理的小鼠的后肢和全肢握力水平接近WT小鼠的水平，以及后肢轻瘫和挛缩的消融。这伴随着坐骨神经轴突包裹和髓鞘形成的恢复。肌肉组织学的改善在表达肌肉特异性αLNNd的小鼠中明显，但在表达αLNNdΔG2'的小鼠中更为广泛。结果表明，αLN接头小基因，在一个无处不在的推动者的推动下，由于其延伸到周围神经的较高表达，因此优于肌肉特异性递送。这些研究支持体细胞基因治疗的潜在新方法。
