Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy.
Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy.
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DOI：
10.1089/hum.2017.062
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发表时间：
2018-07
影响因子：
4.2
通讯作者：
Rodino-Klapac LR
中科院分区：
文献类型：
--
作者：
Potter RA;Griffin DA;Sondergaard PC;Johnson RW;Pozsgai ER;Heller KN;Peterson EL;Lehtimäki KK;Windish HP;Mittal PJ;Albrecht DE;Mendell JR;Rodino-Klapac LR
dysferlin病包括由dysferlin（DYSF）基因突变引起的疾病家族，导致以慢性肌纤维损失、脂肪替代和纤维化为特征的进行性营养不良。为了纠正潜在的组织病理学和功能，需要表达全长DYSF。已经开发了双重腺相关病毒载体，其由同源性区域定义，以用作重建完整的6.5 kb dysferlin cDNA的底物。以前的工作研究了这种治疗通过肌内和区域递送途径的功效。为了使临床疗效最大化，对dysferlin缺陷小鼠进行全身治疗，以通过脉管系统靶向所有肌肉，用于疗效和安全性研究。在治疗后4至13个月之间的多个时间点，使用磁共振成像和磁共振光谱和膜修复来评价小鼠的dysferlin表达和功能改善。全身剂量为6 × 1012个载体基因组导致肌肉中广泛的基因表达。处理的肌肉显示出中心成核、胶原沉积的显著减少，以及膜修复至野生型水平的改善。与安慰剂治疗的肌肉相比，治疗的臀肌肌肉显著改善，并且使用磁共振成像和磁共振波谱法在体积、肌细胞内和肌细胞外脂质积聚和脂肪百分比方面与野生型相当。双载体处理允许产生无毒性的全长功能性dysferlin。这证实了先前的安全性数据，并验证了dysferlin病患者的全身基因递送的翻译。
Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene, leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement, and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is required. Dual adeno-associated virus vectors have been developed, defined by a region of homology, to serve as a substrate for reconstitution of the full 6.5 kb dysferlin cDNA. Previous work studied the efficacy of this treatment through intramuscular and regional delivery routes. To maximize clinical efficacy, dysferlin-deficient mice were treated systemically to target all muscles through the vasculature for efficacy and safety studies. Mice were evaluated at multiple time points between 4 and 13 months post treatment for dysferlin expression and functional improvement using magnetic resonance imaging and magnetic resonance spectroscopy and membrane repair. A systemic dose of 6 × 1012 vector genomes resulted in widespread gene expression in the muscles. Treated muscles showed a significant decrease in central nucleation, collagen deposition, and improvement of membrane repair to wild-type levels. Treated gluteus muscles were significantly improved compared to placebo-treated muscles and were equivalent to wild type in volume, intra- and extramyocellular lipid accumulation, and fat percentage using magnetic resonance imaging and magnetic resonance spectroscopy. Dual-vector treatment allows for production of full-length functional dysferlin with no toxicity. This confirms previous safety data and validates translation of systemic gene delivery for dysferlinopathy patients.
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影响因子：
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