Nongenotoxic conditioning for HIV cure transplantation approaches

HIV治愈移植方法的非基因毒性调理

基本信息

  • 批准号:
    10601077
  • 负责人:
  • 金额:
    $ 22.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-15 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Abstract The cure of HIV using hematopoietic stem cell (HSC) transplant is supported from the experience of the `Berlin patient'. Recent results from patients in London and Düsseldorf are very encouraging and potentially bolster transplant as a cure for HIV. What remains a challenge is to reduce the complexity of hematopoietic stem cell transplant so that it may be more readily adopted in settings that are not acutely life threatening such as chronic HIV disease. Gene editing will make autologous cell transplant possible thereby eliminating the devastating complication of graft versus host disease and address limited availability of allogeneic CCR5 ∆32/∆32 donors. However, `conditioning' to enable stem cells to engraft the marrow is highly toxic and requires resource intensive hospitalization as currently practiced. We aim to develop nongenotoxic conditioning (NGC) that leverages antibody drug conjugates (ADCs) to specifically target and deplete hematopoietic cell populations as a niche sparing method with reduced toxicity. By investigating ADCs that are HSPC-specific (anti-CD117 targeting) or more broadly immune depleting (anti-CD45 targeting), we aim to identify the optimal NGC strategy for enabling efficient HSC transplant in immunodeficiencies. We will combine our ADC-based conditioning with autologous gene-modified cell transplants in animal infection models to identify a lead strategy with translational value. The specific aims of this project are: Specific aim 1. Optimize the dose and schedule of treating NHP with anti-CD117 ADC to achieve durable donor chimerism. Specific aim 2. Optimize the dose and schedule of treating NHP with anti-CD45 ADC to achieve durable donor chimerism. Specific aim 3. Determine whether nongenotoxic conditioning and gene-modified HSC transplant enable disease control in infected animals. If successful, this project will provide specific interventions that can lower the barrier for gene modified HSC transplantation as an approach to cure HIV/AIDS.
摘要 使用造血干细胞(HSC)移植治疗HIV得到了以下方面的支持: “柏林病人”的经历。最近来自伦敦和杜塞尔多夫患者的结果非常 鼓励并可能支持移植作为治疗艾滋病毒的方法。仍然存在的挑战是, 降低造血干细胞移植的复杂性,使其更容易被采用 在不严重威胁生命的环境中,如慢性艾滋病。基因编辑将 使自体细胞移植成为可能,从而消除了移植的毁灭性并发症, 抗宿主疾病的研究,并解决了同种异体CCR 5 β 32/β 32供体的有限可用性。然而,在这方面, 使干细胞能够植入骨髓的“条件作用”具有高度毒性,需要资源 目前实行的集中住院治疗。 我们的目标是开发利用抗体药物偶联物的非遗传毒性调节(NGC (ADC)特异性靶向和消耗造血细胞群体作为小生境保留, 降低毒性的方法。通过研究HSPC特异性ADC(抗CD 117 靶向)或更广泛的免疫耗竭(抗CD 45靶向),我们的目标是确定最佳的 NGC策略使免疫缺陷患者能够进行有效的HSC移植。我们将联合收割机 在动物感染中使用自体基因修饰的细胞移植的基于ADC的预处理 模型来确定具有转化价值的领先战略。该项目的具体目标是: 具体目标1.优化抗CD 117 ADC治疗NHP的剂量和方案, 持久的供体嵌合体 具体目标2。优化抗CD 45 ADC治疗NHP的剂量和方案, 持久的供体嵌合体 具体目标3。确定非遗传毒性调节和基因修饰的HSC 移植使得能够在受感染动物中控制疾病。 如果成功,该项目将提供具体的干预措施,可以降低基因治疗的障碍。 改良HSC移植作为治疗HIV/AIDS的方法。

项目成果

期刊论文数量(0)
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Glen D Raffel其他文献

Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Shows Rapid Primary Engraftment with CD33-Negative Hematopoiesis in Patients with High-Risk Acute Myeloid Leukemia (AML) and Avoids Hematopoietic Toxicity during Gemtuzumab Ozogamicin (GO) Maintenance Post-Hematopoietic Cell Transplant (HCT)
  • DOI:
    10.1182/blood-2023-190037
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    John DiPersio;Brenda W Cooper;Hyung C Suh;Divya Koura;Lea Bernard;Nirali N. Shah;Roland B. Walter;Miguel-Angel Perales;Markus Mapara;Roni Tamari;Michael R. Loken;Kyle Breitschwerdt;Sritama Nath;Glen D Raffel;Guenther Koehne
  • 通讯作者:
    Guenther Koehne
A CD33-Deleted Allograft (Trem-cel) Enables Post-Hematopoietic Cell Transplant (HCT) Maintenance Dosing of Gemtuzumab Ozogamicin (GO) with Therapeutic Levels of Drug Exposure and Low Hematologic and Hepatic Toxicity in Patients with High-Risk Acute Myeloid Leukemia (AML)
  • DOI:
    10.1182/blood-2024-205641
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    John F. DiPersio;Guenther Koehne;Nirali N. Shah;Lea Bernard;Hyung C Suh;Divya Koura;Miguel Angel Perales;Roni Tamari;Muhammad Umair Mushtaq;Joseph E. Maakaron;Michael R. Loken;Darren A Stanizzi;Melissa M. Lee-Sundlov;Sanjana Thosar;Sharon L Hyzy;Glen D Raffel;Brenda W Cooper
  • 通讯作者:
    Brenda W Cooper

Glen D Raffel的其他文献

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{{ truncateString('Glen D Raffel', 18)}}的其他基金

Nongenotoxic conditioning for HIV cure transplantation approaches
HIV治愈移植方法的非基因毒性调理
  • 批准号:
    10163910
  • 财政年份:
    2020
  • 资助金额:
    $ 22.33万
  • 项目类别:
Nongenotoxic conditioning for HIV cure transplantation approaches
HIV治愈移植方法的非基因毒性调理
  • 批准号:
    10409804
  • 财政年份:
    2020
  • 资助金额:
    $ 22.33万
  • 项目类别:
Hematopoietic regulation through Ott1-dependent alternative splicing
通过 Ott1 依赖的选择性剪接进行造血调节
  • 批准号:
    8708200
  • 财政年份:
    2013
  • 资助金额:
    $ 22.33万
  • 项目类别:
Hematopoietic regulation through Ott1-dependent alternative splicing
通过 Ott1 依赖的选择性剪接进行造血调节
  • 批准号:
    8579535
  • 财政年份:
    2013
  • 资助金额:
    $ 22.33万
  • 项目类别:
Mouse model of infant acute megakaryocytic leukemia
婴儿急性巨核细胞白血病小鼠模型
  • 批准号:
    7336370
  • 财政年份:
    2005
  • 资助金额:
    $ 22.33万
  • 项目类别:
Mouse model of infant acute megakaryocytic leukemia
婴儿急性巨核细胞白血病小鼠模型
  • 批准号:
    7176783
  • 财政年份:
    2005
  • 资助金额:
    $ 22.33万
  • 项目类别:
Mouse model of infant acute megakaryocytic leukemia.
婴儿急性巨核细胞白血病小鼠模型。
  • 批准号:
    7008162
  • 财政年份:
    2005
  • 资助金额:
    $ 22.33万
  • 项目类别:
Mouse model of infant acute megakaryocytic leukemia
婴儿急性巨核细胞白血病小鼠模型
  • 批准号:
    6851221
  • 财政年份:
    2005
  • 资助金额:
    $ 22.33万
  • 项目类别:
Mouse model of infant acute megakaryocytic leukemia
婴儿急性巨核细胞白血病小鼠模型
  • 批准号:
    7563228
  • 财政年份:
    2005
  • 资助金额:
    $ 22.33万
  • 项目类别:
Nongenotoxic conditioning for HIV cure transplantation approaches
HIV治愈移植方法的非基因毒性调理
  • 批准号:
    9891829
  • 财政年份:
  • 资助金额:
    $ 22.33万
  • 项目类别:

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