Development of Novel Small Molecule Anti-Fibrotic Agent for the Treatment of Systemic Scleroderma
治疗系统性硬皮病的新型小分子抗纤维化药物的开发
基本信息
- 批准号:10609109
- 负责人:
- 金额:$ 45.24万
- 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:2023-09-15 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:APLN geneAdipose tissueAffectAgonistAnimalsAnti-Inflammatory AgentsAntigensAreaAutoimmune ResponsesBiological AssayBiological MarkersBleomycinBlindedBody WeightCellsCessation of lifeChronicCicatrixCoculture TechniquesCollaborationsCollagenCutaneousDataDermalDevelopmentDiagnosisDiffuseDiseaseDisease modelDoseEndothelial CellsEndotheliumExtracellular MatrixFaceFailureFibrosisFundingGene ExpressionGene Expression ProfilingGoalsGrantHandHeartHistopathologyHumanHuman CharacteristicsHydroxyprolineImmuneImmune responseImmunosuppressive AgentsInflammationInjuryInterleukin-6InternationalInterstitial Lung DiseasesKidneyLeadLungLung Lavage FluidMeasurementMeasuresMediatingMedicalModelingMonoclonal AntibodiesMusMyocardial InfarctionOral AdministrationOrganOrgan Culture TechniquesOrphan DrugsOsmosisPathogenesisPathogenicityPathologistPathway interactionsPatientsPersonsPharmaceutical PreparationsPharmacologyPharmacotherapyPhasePhysical therapyProductionPrognosisPulmonary FibrosisPulmonary Function Test/Forced Expiratory Volume 1PumpQuality of lifeRare DiseasesRattusResearchRheumatismRiskRodent ModelSclerodermaSeverity of illnessSignal PathwaySkinSkin TissueSmall Business Technology Transfer ResearchStructure of parenchyma of lungSurrogate MarkersSystemSystemic SclerodermaSystemic TherapyTestingTherapeuticTherapeutic InterventionThickTissue ModelTissuesToxic effectTyrosine Kinase InhibitorUnited StatesVascular Endothelial CellVascular EndotheliumVascular regenerationWeightantifibrotic treatmentarmcell injurycell regenerationclinical candidatecytokinedisabilitydisorder subtypedrug candidatedrug developmentefficacy studyendothelial regenerationendothelial repairhigh riskhuman tissueidiopathic pulmonary fibrosisimprovedin vivoloss of functionmortalitymortality riskmouse modelnintedanibnovelnovel therapeuticspre-clinicalpreventprimary endpointreceptorregenerativerenal damagerepairedresponseresponse biomarkerskin fibrosissmall moleculesuccesssymptom treatmenttocilizumab
项目摘要
ABSTRACT
The goal of this STTR proposal is to develop a novel anti-fibrotic agent suitable for oral administration which
could be used to safely and effectively treat Systemic Sclerosis (SSc), or Systemic Scleroderma patients. SSc
is one of the most disabling and lethal immune-mediated rheumatic disorders. SSc is a rare disease, affecting
40,000-150,000 people in the United States and conferring a five to eight-fold higher risk for mortality. It is a
heterogeneous, multiorgan disease characterized by vascular endothelial alterations that results in chronic
inflammation and immune responses leading to progressive fibrosis and organ(s) failure. Major impacted organs
are skin, lungs, kidneys, and vasculature system. In SSc patients, vascular endothelial cell injury
characteristically precedes inflammation and autoimmune responses that stimulates the progression into tissue
fibrosis scaring. The leading cause of early death (5 years from diagnosis) is interstitial lung disease (ILD).
Treatment routinely relies on Nintedanib (TK inhibitor) and Tocilizumab (IL-6 mAb), and symptomatic treatments
but these have limited efficacy, and tolerability and/or toxicity issues. As of today, disease fibrosis progression
and mortality rate for SSc remains greater than for any other rheumatic disease; highlighting the clear unmet
medical need for disease modifying therapies that will prevent or reduce the damage to major organs. Targeting
repair and regeneration of the vascular endothelial cell injury via the Apelinergic System (apelin/APJ) signaling
pathway provides a unique and novel opportunity for the treatment of SSc patients (as of today vascular
endothelium repair and regeneration is an under targeted area in SSc drug development). The system is well-
established as an endogenous anti-injury and organ-protective mechanism that is activated post vascular
endothelium injury and is expressed in all SSc disease impacted organs.
APIE Therapeutics, in collaboration with RTI International, has identified a lead anti-fibrotic drug
candidate, apelin agonist APT101, for the treatment of lung fibrosis. First, in a bleomycin-induced lung fibrosis
mouse model therapeutic treatment with APT101 significantly inhibited the production of collagen in the lungs (a
hallmark of lung fibrosis progression), as detected via the Hydroxyproline Assay, and primary end point of the
study. Second, APT101 showed significantly reduced fibrosis in myocardial infarction animal studies (mice and
rats) and significantly reduced biomarker responses in ex-vivo human cell co-culture disease models relevant to
lung, skin, and kidney fibrotic diseases. Taken together, this evidence suggests that activation of the apelinergic
system has the potential to disrupt the pathogenic cascade responsible for progressive fibrosis in SSc. Our aims
for this proposal are obtain preclinical data in validated SSc models: 1) in-vivo efficacy model and, 2) ex-vivo
human tissue model. The results from Aims 1 and 2 will inform a data driven decision regarding APT101 IND
initial indication and subsequent plans for Phases II proposal.
摘要
这项建议的目标是开发一种适用于口服的新型抗纤维化药物,该药物
可用于安全有效地治疗系统性硬化症(SSC)或系统性硬皮病患者。SSC
是最具致残性和致命性的免疫介导的风湿性疾病之一。SSc是一种罕见的疾病,影响
在美国有40,000-150,000人,死亡风险增加五到八倍。这是一个
以血管内皮细胞改变为特征的异质性多器官疾病,导致慢性
炎症和免疫反应导致进行性纤维化和器官衰竭(S)。主要受累器官
皮肤、肺、肾脏和血管系统。在SSc患者中,血管内皮细胞损伤
特点是先于炎症和自身免疫反应,刺激组织的进展
纤维化症。早期死亡的主要原因是间质性肺病(ILD)。
常规治疗依赖于宁替达尼(TK抑制剂)和Tocilizumab(IL-6单抗),以及对症治疗
但这些药物的疗效有限,耐受性和/或毒性问题。截至今天,疾病纤维化进展
SSC的死亡率仍然高于任何其他风湿病;突出了明显的未满足
医学上需要疾病修正疗法,以防止或减少对主要器官的损害。瞄准
APELIN/APJ信号通路对血管内皮细胞损伤的修复与再生
PATH为SSc患者的治疗提供了独特的新机会(截至今天的血管
内皮修复和再生是SSC药物开发中的一个靶向不足的领域)。这个系统很好地-
作为血管后激活的内源性抗损伤和器官保护机制而建立的
内皮细胞损伤,并在所有受SSc疾病影响的器官中表达。
APIE治疗公司与RTI国际公司合作,已经确定了一种主要的抗纤维化药物
候选药物apelin激动剂APT101,用于治疗肺纤维化。首先,在博莱霉素诱导的肺纤维化中
APT101对小鼠模型的治疗显著抑制了肺组织中胶原的产生(A
肺纤维化进展的标志),如通过羟脯氨酸检测,和主要终点
学习。其次,APT101在心肌梗死动物研究中显示显著减少纤维化(小鼠和
在体外人类细胞共培养疾病模型中显著降低了生物标记物的反应
肺、皮肤和肾脏纤维性疾病。综上所述,这一证据表明,apeline能的激活
该系统有可能破坏导致SSc进行性纤维化的病原级联反应。我们的目标
对于这一建议,我们在经过验证的SSC模型中获得了临床前数据:1)体内疗效模型,2)体外
人体组织模型。AIMS 1和AIMS 2的结果将为APT101 Ind的数据驱动决策提供信息
第二阶段提案的初步指示和后续计划。
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 }}
Esther M Alegria其他文献
Esther M Alegria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
Deciphering the role of adipose tissue in common metabolic disease via adipose tissue proteomics
通过脂肪组织蛋白质组学解读脂肪组织在常见代谢疾病中的作用
- 批准号:
MR/Y013891/1 - 财政年份:2024
- 资助金额:
$ 45.24万 - 项目类别:
Research Grant
ESTABLISHING THE ROLE OF ADIPOSE TISSUE INFLAMMATION IN THE REGULATION OF MUSCLE MASS IN OLDER PEOPLE
确定脂肪组织炎症在老年人肌肉质量调节中的作用
- 批准号:
BB/Y006542/1 - 财政年份:2024
- 资助金额:
$ 45.24万 - 项目类别:
Research Grant
Canadian Alliance of Healthy Hearts and Minds: Dissecting the Pathways Linking Ectopic Adipose Tissue to Cognitive Dysfunction
加拿大健康心灵联盟:剖析异位脂肪组织与认知功能障碍之间的联系途径
- 批准号:
479570 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:
Operating Grants
Determinants of Longitudinal Progression of Adipose Tissue Inflammation in Individuals at High-Risk for Type 2 Diabetes: Novel Insights from Metabolomic Profiling
2 型糖尿病高危个体脂肪组织炎症纵向进展的决定因素:代谢组学分析的新见解
- 批准号:
488898 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:
Operating Grants
Activation of human brown adipose tissue using food ingredients that enhance the bioavailability of nitric oxide
使用增强一氧化氮生物利用度的食品成分激活人体棕色脂肪组织
- 批准号:
23H03323 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of new lung regeneration therapies by elucidating the lung regeneration mechanism of adipose tissue-derived stem cells
通过阐明脂肪组织干细胞的肺再生机制开发新的肺再生疗法
- 批准号:
23K08293 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A study on the role of brown adipose tissue in the development and maintenance of skeletal muscles
棕色脂肪组织在骨骼肌发育和维持中作用的研究
- 批准号:
23K19922 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Adipose Tissue T Cell Polarization and Metabolic Health in Persons Living with HIV
HIV 感染者的脂肪组织 T 细胞极化和代谢健康
- 批准号:
10619176 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:
Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation
下丘脑腹内侧区的雌激素信号调节脂肪组织代谢适应
- 批准号:
10604611 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:
Obesity and Childhood Asthma: The Role of Adipose Tissue
肥胖和儿童哮喘:脂肪组织的作用
- 批准号:
10813753 - 财政年份:2023
- 资助金额:
$ 45.24万 - 项目类别:














{{item.name}}会员




