Development of an Effective Strategy to Block Nab Activity for AAV Brain Transduction

开发一种有效策略来阻断 AAV 脑转导的 Nab 活性

基本信息

  • 批准号:
    10600969
  • 负责人:
  • 金额:
    $ 26.96万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Adeno-associated virus (AAV) vectors have been successfully employed in patients with rare neurological diseases. Recently, two AAV based gene therapy drugs have been approved by the FDA, Luxturna been valued at $850,000 with a one-time application for blindness and Zolgensma at $2,100,000 for spinal muscle atrophy. AAV vector mediated gene therapy has shown to be a potentially huge market. Although successful in clinical studies for neurological disorders, one of the major concerns for effective AAV brain application is high prevalence of neutralizing antibody (Nab) in humans. In the general human population, over 95 % of individuals are infected by AAV and, on average, 50 % of them develop Nabs. The inhibition effect of Nabs on AAV brain transduction has been well documented regardless of delivery routes (direct intra-brain injection or systemic administration). Several approaches have been exploited to escape AAV Nabs, including chemical modification, use of different AAV vector serotypes, AAV capsid engineering, and biological depletion of Nab titer (empty capsid utilization, B cell depletion, plasma-apheresis, and Ig proteases). Generally, these approaches have low efficiency, unwanted side effects, or AAV tropism change. Recently, Nabgen has developed a vector independent protein-based strategy to universally block Nabs using a unique mycoplasma derived protein, termed Protein-M. Protein-M is able to interact with immunoglobulin from any species without antigen dependence by binding to variable regions on the antibody light and heavy chains. Using human IVIG and serum from AAV immunized mice, we have found that Protein-M reduced AAV vector neutralization over 100 fold when compared to control group without Protein-M in vitro. Most importantly, we have observed that Protein-M was able to retain AAV transduction over 1000 fold in mice with adoptive transfer of Nab positive serum. So far, this is the most effective strategy to evade AAV Nabs. To explore the application of Protein-M in patients with AAV brain targeted therapy, it is imperative to address the efficacy of Protein-M to protect AAV from Nabs for brain transduction in subjects with Nabs. In this proposal, we will first study the effect of Protein- M co-administered with AAV vectors on AAV Nab blockage via direct injection into the brain in mice with pre- immunization of AAV (Aim 1). Next, we will study the effect of Protein-M via systemic injection on brain transduction after direct delivery of AAV vectors (Aim 2). If successful, this novel and effective technology will extend the benefits of AAV targeted gene therapy to every patient with brain disorders and AAV Nabs.
腺相关病毒(AAV)载体已成功应用于罕见的神经系统疾病患者

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Charles H Askew其他文献

Charles H Askew的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
  • 批准号:
    10682121
  • 财政年份:
    2023
  • 资助金额:
    $ 26.96万
  • 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
  • 批准号:
    10576370
  • 财政年份:
    2022
  • 资助金额:
    $ 26.96万
  • 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
  • 批准号:
    10387023
  • 财政年份:
    2022
  • 资助金额:
    $ 26.96万
  • 项目类别:
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
  • 批准号:
    10248409
  • 财政年份:
    2019
  • 资助金额:
    $ 26.96万
  • 项目类别:
A phase I clinical study of adoptive transfer of regulatory T cells (Tregs) and low-dose interleukin-2 (IL-2) for the treatment of chronic graft-versus-host disease (GVHD): gene-marking to inform rational combination therapy
调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
  • 批准号:
    nhmrc : GNT1163111
  • 财政年份:
    2019
  • 资助金额:
    $ 26.96万
  • 项目类别:
    Project Grants
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
  • 批准号:
    10462684
  • 财政年份:
    2019
  • 资助金额:
    $ 26.96万
  • 项目类别:
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
基因编辑的淋巴祖细胞用于过继转移作为原发性免疫缺陷的治疗
  • 批准号:
    398018062
  • 财政年份:
    2018
  • 资助金额:
    $ 26.96万
  • 项目类别:
    Research Grants
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
  • 批准号:
    9308643
  • 财政年份:
    2017
  • 资助金额:
    $ 26.96万
  • 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
  • 批准号:
    9447149
  • 财政年份:
    2017
  • 资助金额:
    $ 26.96万
  • 项目类别:
Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes
通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA
  • 批准号:
    8893915
  • 财政年份:
    2014
  • 资助金额:
    $ 26.96万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了