Efficacy of Gene Therapy Is Dependent on Disease Progression in Dystrophic Mice with Mutations in the FKRP Gene.
Efficacy of Gene Therapy Is Dependent on Disease Progression in Dystrophic Mice with Mutations in the FKRP Gene.
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DOI：
10.1016/j.omtm.2017.02.002
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发表时间：
2017-06-16
期刊：
影响因子：
--
通讯作者：
Lu QL
中科院分区：
文献类型：
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作者：
Vannoy CH;Xiao W;Lu P;Xiao X;Lu QL
Fukutin相关蛋白（FKRP）基因的功能缺失突变导致肢带型肌营养不良2 I型（LGMD 2 I）和其他形式的先天性肌营养不良-肌营养不良聚糖病，这些疾病与α-肌营养不良聚糖（α-DG）蛋白的糖基化缺陷相关。评估了在疾病进展的各个阶段向LGMD 2 I小鼠模型全身给予单剂量表达人FKRP的重组腺相关病毒血清型9（AAV 9）载体的情况。结果表明，与年龄匹配的未治疗队列相比，α-DG的功能性糖基化和肌肉功能得到了挽救，沿着所有疾病阶段的肌肉结构改善。然而，在疾病进展的后期阶段接受治疗的小鼠显示治疗的有益效果减少。这些结果为FKRP相关肌营养不良症患者的未来临床试验提供了概念证明，并表明AAV介导的基因治疗可能使疾病进展的所有阶段的患者受益，但早期干预是非常优选的。
Loss-of-function mutations in the Fukutin-related protein (FKRP) gene cause limb-girdle muscular dystrophy type 2I (LGMD2I) and other forms of congenital muscular dystrophy-dystroglycanopathy that are associated with glycosylation defects in the α-dystroglycan (α-DG) protein. Systemic administration of a single dose of recombinant adeno-associated virus serotype 9 (AAV9) vector expressing human FKRP to a mouse model of LGMD2I at various stages of disease progression was evaluated. The results demonstrate rescue of functional glycosylation of α-DG and muscle function, along with improvements in muscle structure at all disease stages versus age-matched untreated cohorts. Nevertheless, mice treated in the latter stages of disease progression revealed a decrease in beneficial effects of the treatment. The results provide a proof of concept for future clinical trials in patients with FKRP-related muscular dystrophy and demonstrate that AAV-mediated gene therapy can potentially benefit patients at all stages of disease progression, but earlier intervention would be highly preferred.