Recombinant Adeno Associated Virus Vectors for Gene Transfer

用于基因转移的重组腺相关病毒载体

基本信息

项目摘要

DMD, an X-linked recessive disorder, is the most frequent hereditary myopathy affecting approximately 1 in 3500 boys of all races. It is caused by mutations in the gene for the myocyte structural protein dystrophin. The loss of functional dystrophin in striated muscles causes extreme myocyte fragility and damage. The skeletal muscles degenerate continuously becoming fibrotic with adipose infiltrates. Clinical symptoms first manifest in boys between 18 months and 3 years of age. Muscle wasting occurs as the disease progresses and the patients become nonambulatory between 9 to 12 years of age. Mortality results from continuous loss of skeletal muscle causing spinal deformation, breathing difficulties, and cardiomyopathies. The disease is always fatal, often in the second decade and invariably in the third decade of life. There are no cures for DMD, and the current therapeutics regimens involve steroidal anti-inflamatories to limit immune responses to muscle fiber damage and only palliative treatments. Recombinant AAV may be used to restore dystrophin expression to skeletal muscles, either using a protein replacement approach, e.g. vectors that express micro-dystrophin, or an exon-skipping approach. For either application, producing sufficient quantities of rAAV to attain meaningful endpoints in the clinically relevant canine model of DMD has been the major obstacle for clinical trials. Most of the rAAV vector we produce contain a non-structural gene expressing a modified U7 RNA that interferes with processing the primary dystrophin transcript. Using specific anti-sense elements, our collaborators determined that specific exons may be omitted from the mature mRNA. This exon-skipping approach has been validated in murine DMD models and limited trials in canine DMD models. Based on these encouraging results, studies are underway using rAAV that express reporter proteins to establish the pharmacological parameters for treating DMD. From these results, the bio-distribution, routes of administration, vector toxicity are determined. Finally, using the data obtained with reporter constructs, doses that produce phenotypic improvements in large animals DMD models can then be established.
DMD 是一种 X 连锁隐性遗传病,是最常见的遗传性肌病,大约每 3500 名男孩中就有 1 名受到影响。它是由肌细胞结构蛋白肌营养不良蛋白基因突变引起的。横纹肌功能性肌营养不良蛋白的丧失会导致心肌细胞极度脆弱和损伤。骨骼肌不断退化,纤维化并伴有脂肪浸润。临床症状首先出现在 18 个月至 3 岁的男孩中。随着疾病的进展,患者在 9 至 12 岁之间变得无法行走,就会出现肌肉萎缩。骨骼肌持续丧失导致脊柱变形、呼吸困难和心肌病,导致死亡。这种疾病总是致命的,通常发生在生命的第二个十年,而且总是在生命的第三个十年。 DMD 无法治愈,目前的治疗方案包括使用类固醇抗炎药来限制对肌肉纤维损伤的免疫反应,并且仅进行姑息治疗。 重组 AAV 可用于恢复骨骼肌肌营养不良蛋白的表达,可以使用蛋白质替​​代方法,例如表达微肌营养不良蛋白的载体,或外显子跳跃方法。对于这两种应用,生产足够数量的 rAAV 以在临床相关的 DMD 犬模型中达到有意义的终点一直是临床试验的主要障碍。我们生产的大多数 rAAV 载体都含有表达修饰的 U7 RNA 的非结构基因,该基因会干扰初级肌营养不良蛋白转录物的加工。使用特定的反义元件,我们的合作者确定特定的外显子可以从成熟的 mRNA 中省略。 这种外显子跳跃方法已在小鼠 DMD 模型中得到验证,并在犬 DMD 模型中进行了有限的试验。基于这些令人鼓舞的结果,正在使用表达报告蛋白的 rAAV 进行研究,以确定治疗 DMD 的药理学参数。根据这些结果,可以确定生物分布、给药途径、载体毒性。最后,利用报告构建体获得的数据,可以确定在大型动物 DMD 模型中产生表型改善的剂量。

项目成果

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Robert Kotin其他文献

Robert Kotin的其他文献

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{{ truncateString('Robert Kotin', 18)}}的其他基金

Characterization Of Adeno Associated Virus Non-structura
腺相关病毒非结构的表征
  • 批准号:
    6546774
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Recombinant Adeno Associated Virus
重组腺相关病毒
  • 批准号:
    6546775
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Characterization Of Adeno Associated Virus Non-structura
腺相关病毒非结构的表征
  • 批准号:
    6817837
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Characterization Of Adeno Associated Virus Non-structura
腺相关病毒非结构的表征
  • 批准号:
    6690525
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Recombinant Adeno Associated Virus Vectors for Gene Transfer
用于基因转移的重组腺相关病毒载体
  • 批准号:
    8746559
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Characterization Of Adeno Associated Virus Non-structura
腺相关病毒非结构的表征
  • 批准号:
    7321586
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Characterization Of Adeno Associated Virus Non-structura
腺相关病毒非结构的表征
  • 批准号:
    7154392
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Recombinant Adeno Associated Virus
重组腺相关病毒
  • 批准号:
    7157865
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
Recombinant Adeno Associated Virus
重组腺相关病毒
  • 批准号:
    6966931
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:
CHARACTERIZATION OF ADENO ASSOCIATED VIRUS NON-STRUCTURAL PROTEINS
腺相关病毒非结构蛋白的表征
  • 批准号:
    6432678
  • 财政年份:
  • 资助金额:
    $ 222.81万
  • 项目类别:

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地方政府统一开展3岁儿童健康检查发育筛查工作的开展及社会实施
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  • 批准号:
    ES/W001020/1
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