Neutralization of ceramide as a novel approach to specifically inhibit acute GvHD

神经酰胺中和作为特异性抑制急性 GvHD 的新方法

基本信息

  • 批准号:
    8395366
  • 负责人:
  • 金额:
    $ 28.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-01 至 2014-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Acute graft-versus-host disease (GvHD) is a primary complication of allogeneic stem cell transplantation, associated with wasting, immunosuppression and specific damage to the intestines, liver and skin. GvHD results from activation of donor T cells from human leukocyte antigen (HLA)-identical or related donors against host tissues. Current therapeutic approaches to mitigate the basic underlying pathology of acute GvHD include immune-suppressive drugs or depletion of T cells from the graft, however these options render severely immunocompromised patients susceptible to infection or neoplastic relapse. As such, attenuation of GvHD- associated pathology while maintaining immune function against residual malignancy or infection is the 'holy grail' of HCST adjuvant therapies. Ceramide Therapeutics proposes the generation and development of anti- ceramide monoclonal IgG antibody as a mechanism-based approach to protect host tissue and prevent or treat acute GvHD. Evidence that ceramide regulates tissue pathophysiology during acute GvhD was obtained using mice deficient in acid sphingomyelinase (ASMase)-mediated ceramide generation as hosts for minor antigen mismatched bone marrow and T cells. Inactivation of host ASMase abrogated tissue damage during GvHD and attenuated the inflammatory response responsible for propagating CTL attack of host tissue, thereby significantly improving survival in mouse models. Investigation into the mechanism of action of hepatocyte apoptosis during GvHD revealed that CTLs induce ceramide generation on the target hepatocyte surface, driving the biophysical reorganization of the exoplasmic membrane into structures called ceramide-rich platforms (CRPs). CRPs are sites where transmembrane apoptotic signal transduction takes place, and are amenable to pharmacologic inactivation. In the current application, we propose to generate a high-affinity neutralizing anti-ceramide IgG for advancement into preclinical development. PUBLIC HEALTH RELEVANCE: Inhibition of acute GvHD-associated pathophysiology while maintaining global immune functioning against residual malignancy and infection is the 'holy grail' of HCST adjuvant therapies. Ceramide regulates tissue pathophysiology during acute GvhD, as genetic deletion of acid sphingomyelinase (ASMase)-mediated ceramide generation abrogated tissue damage during GvHD, attenuated the inflammatory response responsible for propagating CTL attack of host tissue, and significantly improved survival in mouse models. Here we propose the generation of a high-affinity neutralizing anti-ceramide IgG to specifically inhibit GvHD pathophysiology while not impacting global T cell function, for advancement into preclinical development.
描述(由申请人提供):急性移植抗宿主病(GVHD)是同种异体干细胞移植的主要并发症,与浪费,免疫抑制和对肠道,肝脏和皮肤的特异性损害有关。 GVHD是由对宿主组织的人类白细胞抗原(HLA)或相关供体激活的供体T细胞的激活。当前减轻急性GVHD的基本潜在病理的治疗方法包括免疫抑制药物或T细胞从移植物中耗尽,但是这些选择使人受到严重免疫免疫功能低下的患者感染或肿瘤复发。因此,HCST辅助疗法的“神圣的圣杯”是GVHD相关病理的衰减,同时保持免疫功能是对残留恶性肿瘤或感染的。神经酰胺治疗剂提出了抗神经酰胺单克隆IgG抗体的产生和开发,作为一种基于机制的方法,可保护宿主组织,预防或治疗急性GVHD。神经酰胺在急性GVHD期间调节组织病理生理学的证据是使用缺乏酸性鞘磷脂酶(ASMase)介导的神经酰胺的产生的小鼠作为较小抗原不匹配的骨髓和T细胞的宿主。宿主ASMase的失活消除了GVHD期间的组织损伤,并减弱了负责传播宿主组织CTL攻击的炎症反应,从而显着提高了小鼠模型中的生存​​率。研究GVHD期间肝细胞凋亡的作用机理的研究表明,CTLS在靶标肝细胞表面诱导神经酰胺的产生,将外质膜的生物物理重组驱动为称为富含陶瓷的平台(CRP)的结构。 CRP是发生跨膜凋亡信号转导的部位,并且可与药物失活。在当前的应用中,我们建议生成高亲和力中和抗神经酰胺IgG,以发展临床前发育。 公共卫生相关性:抑制急性GVHD相关的病理生理学,同时维持全球免疫功能,以防止残留恶性肿瘤和感染,是HCST辅助治疗的“圣杯”。急性GVHD期间,神经酰胺调节组织病理生理学,因为酸鞘磷脂酶的遗传缺失(ASMASE)介导的神经酰胺的产生消除了GVHD期间的组织损伤,衰减了炎症反应,导致促进宿主组织的CTL攻击,并在小鼠模型中大大改善生存。在这里,我们提出了高亲和力中和抗神经酰胺IgG的生成,以特别抑制GVHD病理生理学,同时不影响全球T细胞功能,以发展临床前发育。

项目成果

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Jim Rotolo其他文献

Jim Rotolo的其他文献

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{{ truncateString('Jim Rotolo', 18)}}的其他基金

Inhibition of SARS-CoV-2 infection with a pan-coronavirus anti-viral peptide
泛冠状病毒抗病毒肽抑制 SARS-CoV-2 感染
  • 批准号:
    10256216
  • 财政年份:
    2021
  • 资助金额:
    $ 28.48万
  • 项目类别:
Inhibition of SARS-CoV-2 infection with a pan-coronavirus anti-viral peptide
泛冠状病毒抗病毒肽抑制 SARS-CoV-2 感染
  • 批准号:
    10401492
  • 财政年份:
    2021
  • 资助金额:
    $ 28.48万
  • 项目类别:
Development of a cell-penetrating beta-catenin antagonist peptide as a therapeutic candidate for Wnt-driven breast cancer
开发细胞穿透性 β-连环蛋白拮抗剂肽作为 Wnt 驱动乳腺癌的候选治疗药物
  • 批准号:
    10707593
  • 财政年份:
    2021
  • 资助金额:
    $ 28.48万
  • 项目类别:
Development of a cell-penetrating beta-catenin antagonist peptide as a therapeutic candidate for Wnt-driven breast cancer
开发细胞穿透性 β-连环蛋白拮抗剂肽作为 Wnt 驱动乳腺癌的候选治疗药物
  • 批准号:
    10324076
  • 财政年份:
    2021
  • 资助金额:
    $ 28.48万
  • 项目类别:
Efficacy and PK/PD of a C/EBP beta antagonist in orthotopic breast cancer
C/EBP β 拮抗剂在原位乳腺癌中的疗效和 PK/PD
  • 批准号:
    10681209
  • 财政年份:
    2020
  • 资助金额:
    $ 28.48万
  • 项目类别:
Efficacy and PK/PD of a C/EBP beta antagonist in orthotopic breast cancer
C/EBP β 拮抗剂在原位乳腺癌中的疗效和 PK/PD
  • 批准号:
    10079655
  • 财政年份:
    2020
  • 资助金额:
    $ 28.48万
  • 项目类别:
Efficacy and PK/PD of a C/EBP beta antagonist in orthotopic breast cancer
C/EBP β 拮抗剂在原位乳腺癌中的疗效和 PK/PD
  • 批准号:
    10384382
  • 财政年份:
    2020
  • 资助金额:
    $ 28.48万
  • 项目类别:
Single-chain antibody countermeasures for the Radiation GI Syndrome
放射胃肠道综合症的单链抗体对策
  • 批准号:
    8646044
  • 财政年份:
    2014
  • 资助金额:
    $ 28.48万
  • 项目类别:
Single-chain antibody countermeasures for the Radiation GI Syndrome
放射胃肠道综合症的单链抗体对策
  • 批准号:
    8852053
  • 财政年份:
    2014
  • 资助金额:
    $ 28.48万
  • 项目类别:
Neutralization of ceramide as a novel approach to specifically inhibit acute GvHD
神经酰胺中和作为特异性抑制急性 GvHD 的新方法
  • 批准号:
    8514511
  • 财政年份:
    2012
  • 资助金额:
    $ 28.48万
  • 项目类别:

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基于移植后急性移植物抗宿主病智能预警的关键算法与应用研究
  • 批准号:
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  • 批准年份:
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Neutralization of ceramide as a novel approach to specifically inhibit acute GvHD
神经酰胺中和作为特异性抑制急性 GvHD 的新方法
  • 批准号:
    8514511
  • 财政年份:
    2012
  • 资助金额:
    $ 28.48万
  • 项目类别:
ROCK inhibitor suppression of GVHD with retention of GVL response
ROCK 抑制剂抑制 GVHD 并保留 GVL 反应
  • 批准号:
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  • 财政年份:
    2011
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ROCK 抑制剂抑制 GVHD 并保留 GVL 反应
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    $ 28.48万
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Cancer and Leukemia Group B
癌症和白血病 B 组
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    7513241
  • 财政年份:
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  • 资助金额:
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