Rational design of AAV vectors with human hepatocyte tropism and neutralizing antibody evasion

具有人肝细胞趋向性和中和抗体逃避性的AAV载体的合理设计

基本信息

  • 批准号:
    10546241
  • 负责人:
  • 金额:
    $ 26.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Adeno-associated virus (AAV) vectors have been successfully applied in clinical trials in patients with diverse disorders. Two AAV based gene therapy drugs have been recently approved by the FDA. Luxturna has been valued at $850,000 for a one-time treatment for a rare form of blindness and Zolgensma priced at $2,100,000 for spinal muscle atrophy. As such, AAV vector based gene therapy is an increasingly attractive market. Although successful in clinical studies, two concerns restrict broader AAV vector applications for patients requiring liver targeted AAV gene therapy following systemic administration: low human hepatocyte transduction and neutralizing antibody (Nab)-mediated inhibition of AAV transduction. Several approaches have been explored for AAV transduction enhancement or capsid Nab evasion. Engineering of the AAV capsid presents a very powerful and popular technology that has been extensively studied to develop novel AAV vectors for enhanced transduction in animal models or Nab escape in vitro. However, it has been demonstrated that the results from mouse experiments do not recapitulate those of large animals such as primates and dogs. Thus, the data for AAV variants generated in animal cells and organs may not translate into successful human applications. Recently, a mouse xenograft model with human hepatocytes has been used to develop human liver targeted AAV vectors for gene therapy. In our previous studies, we have successfully isolated several AAV mutants from the liver of chimeric mice with human hepatocyte xenografts in the presence of human Nabs (IVIG) using the AAV shuffled capsid library approach. Specifically, BDRK001 (AAV mutant LP2-10) demonstrated a much higher ability to evade Nabs than any other AAV serotypes or mutants. However, BDRK001 was not enhanced for transduction in human hepatocytes when compared to the best natural serotype. In this application, we will use rational design strategy to generate novel AAV capsids by variable region I (VRI) domain swapping of BDRK001 using natural serotypes or mutants with high human liver tropism. This panel will then be evaluated in chimeric mice for human hepatocyte transduction (Aim 1) and Nab evasion (Aim 2). Bedrock's long-term goal of this approach is low dose AAV gene therapy for the successful treatment of a variety of liver diseases, independent of the patient's Nab prevalence.
腺相关病毒(AAV)载体已成功应用于临床试验

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Chengwen Li其他文献

Chengwen Li的其他文献

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{{ truncateString('Chengwen Li', 18)}}的其他基金

Novel strategy to block Nabs for AAV gene delivery
阻断 Nabs 进行 AAV 基因传递的新策略
  • 批准号:
    10570881
  • 财政年份:
    2022
  • 资助金额:
    $ 26.11万
  • 项目类别:
Novel strategy to block Nabs for AAV gene delivery
阻断 Nabs 进行 AAV 基因传递的新策略
  • 批准号:
    10416627
  • 财政年份:
    2022
  • 资助金额:
    $ 26.11万
  • 项目类别:
Development of AAV vectors for CF therapy
用于 CF 治疗的 AAV 载体的开发
  • 批准号:
    10544549
  • 财政年份:
    2020
  • 资助金额:
    $ 26.11万
  • 项目类别:
Development of AAV vectors for CF therapy
用于 CF 治疗的 AAV 载体的开发
  • 批准号:
    10117463
  • 财政年份:
    2020
  • 资助金额:
    $ 26.11万
  • 项目类别:
Develop humanized AAV vectors for liver targeting and neutralizing antibody evasion
开发用于肝脏靶向和中和抗体逃避的人源化 AAV 载体
  • 批准号:
    10079155
  • 财政年份:
    2020
  • 资助金额:
    $ 26.11万
  • 项目类别:
Development of AAV vectors for CF therapy
用于 CF 治疗的 AAV 载体的开发
  • 批准号:
    10319017
  • 财政年份:
    2020
  • 资助金额:
    $ 26.11万
  • 项目类别:
Novel strategy to block AAV neutralizing anitbody activity
阻止 AAV 中和抗体活性的新策略
  • 批准号:
    10080225
  • 财政年份:
    2020
  • 资助金额:
    $ 26.11万
  • 项目类别:
Optimization of AAV vector to deliver FVa for hemophilia with inhibitors
优化 AAV 载体以通过抑制剂递送血友病 FVa
  • 批准号:
    10372097
  • 财政年份:
    2019
  • 资助金额:
    $ 26.11万
  • 项目类别:
Enhance AAV Liver Transduction with Capsid Immune Evasion
通过衣壳免疫逃避增强 AAV 肝脏转导
  • 批准号:
    9098885
  • 财政年份:
    2016
  • 资助金额:
    $ 26.11万
  • 项目类别:
Enhance AAV Liver Transduction with Capsid Immune Evasion
通过衣壳免疫逃避增强 AAV 肝脏转导
  • 批准号:
    9893176
  • 财政年份:
    2016
  • 资助金额:
    $ 26.11万
  • 项目类别:

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