Development of heparan sulfate-based therapeutics to treat inflammatory diseases
开发基于硫酸乙酰肝素的炎症性疾病疗法
基本信息
- 批准号:10324781
- 负责人:
- 金额:$ 23.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-14 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcetaminophenAcuteAcute Liver FailureAddressAnimal SourcesAnti-Inflammatory AgentsAnticoagulantsAntiinflammatory EffectAttenuatedBiological ProcessBloodBlood Coagulation DisordersBrainClinical TrialsComplex MixturesDevelopmentDiseaseDisease modelDrug KineticsDrug or chemical Tissue DistributionFundingGoalsHMGB1 ProteinHeparinHeparitin SulfateHepatotoxicityHospitalsHumanImmune responseInflammationInflammatoryInflammatory ResponseInjuryInvestigationIschemiaKilogramLabelLiver FailureMediatingMetabolic Clearance RateMethodsModelingMonosaccharidesMusNeutrophil InfiltrationOligosaccharidesPatternPeritonitisPharmaceutical PreparationsPhasePlasmaPolysaccharidesPreparationPrincipal InvestigatorProductionPublicationsPublishingReperfusion InjuryReperfusion TherapyReportingRouteSchemeSepsisSeriesSiteSmall Business Innovation Research GrantSourceStructureSulfateTherapeuticTherapeutic AgentsToxic effectTranslational ResearchTraumaUniversitiesUrineWorkacetaminophen overdosebasechemical synthesiscostdesigndrug candidateexperimental studyimprovedinnovationlead candidateliver injuryliver ischemiamouse modelnovel strategiesnovel therapeuticsphase 1 studyphase 2 studypreclinical developmentprogramsreceptor for advanced glycation endproductsscale upscreeningstemsubcutaneoussuccesssugarsystemic inflammatory responsetherapeutic targettranslational medicine
项目摘要
Abstract
The goal of this SBIR phase I project is aimed at completing a larger synthesis scale and
pharmacokinetic studies for 18-mer, a lead candidate anti-inflammatory heparan sulfate
oligosaccharide. 18-mer decreased neutrophil infiltration in murine diseases model of peritonitis,
liver ischemia/reperfusion injury, and acetaminophen-induced acute liver failure (APAP-induced
ALF). 18-mer targets to high mobility group box 1 (HMGB1) protein and attenuates HMGB1-
mediated inflammation characterized by neutrophil infiltration to the injury site. In addition to
these disease models, HMGB1 is involved a numerous local and systemic inflammation
disorders including sepsis and trauma injury. Currently, there are no approved therapeutics
targeting HMGB1-mediated inflammation.
This work is focused on developing 18-mer as a therapeutic for APAP-induced ALF. Confidence
to pursue 18-mer stems from screening experiments using other oligosaccharides in the APAP
model that were ineffective compared to 18-mer and demonstrating 18-mer’s anti-inflammatory
effect is multiple inflammatory mouse models. This SBIR phase I application contains two
specific aims. In Aim 1, we plan to increase the synthetic scale to 10 g, about 30-fold increase
from the current production scale. The improved synthesis will use a 12-mer intermediate as
the starting material, shortening the synthetic steps to 16 from 36. Aim 2 is to develop a LC-
MS/MS based method to quantify the 18-mer in blood and urine. This method will allow us to
obtain pharmacokinetic parameters in the subsequent preclinical development. In the phase II
studies, we will focus on increasing the scale-up synthesis to 100g, IND-enabling studies and
tissue distribution of the oligosaccharides. The success of this project will provide a new
approach to treat drug induced liver toxicity by targeting to HMGB1-mediated inflammation.
摘要
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Heparan sulfates and heparan sulfate binding proteins in sepsis.
- DOI:10.3389/fmolb.2023.1146685
- 发表时间:2023
- 期刊:
- 影响因子:5
- 作者:
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Katelyn Arnold其他文献
Katelyn Arnold的其他文献
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{{ truncateString('Katelyn Arnold', 18)}}的其他基金
Development ofsynthetic heparin to protect liver graft from ischemia reperfusion injury duringtransplantation
开发合成肝素以保护移植肝免受移植过程中的缺血再灌注损伤
- 批准号:
10759102 - 财政年份:2023
- 资助金额:
$ 23.11万 - 项目类别:
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