First-in-class TREM-1 inhibitors for neovascular retinal diseases

用于治疗新生血管性视网膜疾病的一流 TREM-1 抑制剂

基本信息

  • 批准号:
    10597284
  • 负责人:
  • 金额:
    $ 27.81万
  • 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:
    2023-09-30 至 2024-09-29
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Retinal neovascularization (RNV) is a major cause of vision loss in retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion. In the US, about 16,000 of premature infants are affected by ROP annually and about 4.1 million adults years have DR. Complications of conventional treatments suggest an unmet need for new therapies. The long-term objective of this project is to develop a systemic, new mechanism-based, efficient and well-tolerable therapy for ROP and other RNV diseases. Triggering receptor expressed on myeloid cells (TREM-1) is upregulated upon inflammation and is involved in angiogenic signaling pathways, suggesting TREM-1 as a promising target for treatment of RNV. Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To minimize clinical failure risks, we developed well-tolerable TREM-1 inhibitory peptides GF9 and GA31 that employ a novel, ligand-independent mechanism of action. They can be used in a free form or formulated in macrophage-specific lipopeptide complexes (LPC) to improve half-life and reduce off-target risks. Previously, we showed that ligand-independent TREM-1 blockade using either a free (GF9) or LPC- formulated peptide (GA31-LPC): 1) prevents and treats RNV in mice with oxygen-induced retinopathy (OIR); 2) improves vessel sprouting during hypoxia, 3) inhibits retinal TREM-1 and CSF-1 expression, and 4) reduces cytokine release (TNFα, IL-1β, IL-6 and CSF-1) in vitro, while control peptides have no effect. The goal of the proposed project is to further develop this first-in-class TREM-1 therapy for neovascular retinal diseases. Considering pros and cons of GF9 and GA31-LPC, we suggest to start with both leads. Due to differences in the manifestation of vascular phenotypes, we suggest to use both OIR mice and rats. Phase I aims are to: 1) generate GMP-compliant formulations of free GF9 and GA31-LPC and test them in vitro, and 2) test the developed formulations of GF9 and GA31-LPC in the OIR mouse model. GMP-friendly tangential flow filtration technique to prepare GA31-LPC will be explored. Phase II aims are to: 1) develop an LC-MS-assay to measure GF9 and GA31 in ocular tissues, 2) test pharmacokinetics and ocular tissue distribution of GF9 and GA31-LPC in vivo, 3) test the preventative and therapeutic effects of GF9 and GA31-LPC in two OIR models and select the lead, and 4) test the lead in non-clinical toxicology studies. Comprehensive histology/IHC will be performed. Cytokines will be tested. Follow-up Phase IIb will include other administration and combination (eg, laser + GF9) regimens, GLP- TOX, ADME, CMC and other IND-enabling studies. The final product will represent safe and stable systemic therapy. Its anticipated safety is supported by safety of GF9 therapy in long-term treated healthy, cancer and arthritic mice. Prototypes of SignaBlok's LPC are well-tolerated in humans. TREM-1 blockade by SignaBlok competitor's peptide LR12 (Inotrem) is safe and well-tolerated in healthy and septic subjects.
项目总结/文摘

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 }}

Alexander B Sigalov其他文献

Alexander B Sigalov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 }}

{{ truncateString('Alexander B Sigalov', 18)}}的其他基金

New mechanism-based TREM-1 therapy for acute respiratory distress syndrome
基于新机制的 TREM-1 疗法治疗急性呼吸窘迫综合征
  • 批准号:
    10678788
  • 财政年份:
    2023
  • 资助金额:
    $ 27.81万
  • 项目类别:
TREM-1 inhibitor for the treatment of scleroderma
TREM-1抑制剂用于治疗硬皮病
  • 批准号:
    10079840
  • 财政年份:
    2020
  • 资助金额:
    $ 27.81万
  • 项目类别:
TREM-1 therapy for rheumatoid arthritis
TREM-1 治疗类风湿性关节炎
  • 批准号:
    10080141
  • 财政年份:
    2020
  • 资助金额:
    $ 27.81万
  • 项目类别:
First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer
用于胰腺癌联合治疗的一流 TREM-1 抑制剂
  • 批准号:
    9407074
  • 财政年份:
    2017
  • 资助金额:
    $ 27.81万
  • 项目类别:
First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer
用于胰腺癌联合治疗的一流 TREM-1 抑制剂
  • 批准号:
    9984628
  • 财政年份:
    2017
  • 资助金额:
    $ 27.81万
  • 项目类别:
First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer
用于胰腺癌联合治疗的一流 TREM-1 抑制剂
  • 批准号:
    10024061
  • 财政年份:
    2017
  • 资助金额:
    $ 27.81万
  • 项目类别:
First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer
用于胰腺癌联合治疗的一流 TREM-1 抑制剂
  • 批准号:
    9902597
  • 财政年份:
    2017
  • 资助金额:
    $ 27.81万
  • 项目类别:
Novel mechanism-based targeted approach to rheumatoid arthritis
基于新机制的类风湿性关节炎靶向治疗方法
  • 批准号:
    8818617
  • 财政年份:
    2014
  • 资助金额:
    $ 27.81万
  • 项目类别:
Multifunctional nanoformulations for diagnostic imaging of atherosclerosis
用于动脉粥样硬化诊断成像的多功能纳米制剂
  • 批准号:
    8307121
  • 财政年份:
    2012
  • 资助金额:
    $ 27.81万
  • 项目类别:
Development of novel targeted agents in lung cancer
肺癌新型靶向药物的开发
  • 批准号:
    8311498
  • 财政年份:
    2012
  • 资助金额:
    $ 27.81万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
  • 批准号:
    10065645
  • 财政年份:
    2023
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 27.81万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了