Targeting TLR4-lipid rafts to prevent postoperative pain
靶向 TLR4 脂筏预防术后疼痛
基本信息
- 批准号:10701528
- 负责人:
- 金额:$ 41.48万
- 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:2023-09-21 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcute PainAnalgesicsAnimalsApolipoprotein A-IAreaBehaviorBehavioralBindingBinding ProteinsBiological AssayBiological MarkersBloodCancer CenterCancer PatientCell membraneCellsChemotherapy-induced peripheral neuropathyCholesterolClinicClinical TrialsContralateralCyclic GMPDataData SetDay SurgeryDependenceDevelopmentDevelopment PlansDoseDrug KineticsExcisionFemaleFormulationFrightFundingFutureGenerationsGoalsHarvestHospitalsHumanHuman ActivitiesHyperactivityIn VitroIncidenceInflammationInflammatoryInjuryIntravenousIpsilateralLaboratoriesLinkMacrophageMediatingMedicalMembraneMembrane LipidsMembrane MicrodomainsMethodsMicrogliaModelingNeuronsNociceptionNociceptorsNon-Steroidal Anti-Inflammatory AgentsOperative Surgical ProceduresOpioidOrganPainPain managementPatientsPerioperativePeripheralPharmaceutical PreparationsPharmacologic SubstancePhasePhenotypePostoperative PainPrevalenceProceduresProcessProtocols documentationPublishingQuality of lifeRattusRegulationReportingSafetySecondary toSensorySex DifferencesSideSiteSmall Business Technology Transfer ResearchSourceSpinalSpinal CordSpinal GangliaSurgical InjuriesSurgical incisionsSystemTLR4 geneTactileTestingTherapeuticTimeToxicologyTranslatingVariantVertebral columnWithdrawalWorkaddictionadverse outcomeallodyniacancer survivalchronic painclinical developmentcostdermatomedrug candidateefficacy studyfirst-in-humanimmunogenicityin vivointravenous injectionmalemanufacturenerve injuryneuroinflammationnon-opioid analgesicnovelnovel strategiespain modelpain reliefpre-Investigational New Drug meetingpreventresponsesafety assessmentsafety studysafety testingsexside effectspontaneous paintissue injurywound
项目摘要
PROJECT SUMMARY
Postoperative pain is a prevalent source of pain requiring appropriate management to reduce its impact upon
quality of life. Even with the availability of several analgesics, postoperative pain is often undermedicated
because of concern related to the adverse consequence of the available therapeutics (e.g., NSAIDs and opiates),
including addiction and decreased survival of cancer patients. To this end we have undertaken development of
RFT1124, a modified apolipoprotein A-I binding protein (AIBP), which exerts its action through specific targeting
of membrane lipid rafts by altering local membrane cholesterol dynamics in dorsal root ganglion (DRG) neurons
and macrophages and in spinal microglia that express TLR4 (TLR4-rafts) and are known to be engaged in
processing acute and chronic pain secondary to nerve and tissue injury. We have discovered that TLR4-rafts
are heavily expressed on macrophages and exclusively on nociceptive DRG neurons. We have shown that it is
possible to specifically target these TLR4-rafts through the actions of RFT1124 (AIBP), which binds to TLR4 and
specifically disrupts the associated lipid rafts. In vitro, AIBP blocks the ectopic activity of human DRG nociceptors
isolated from painful dermatomes. In vivo, intravenous injection of AIBP prior to paw incision prevented the
development of tactile allodynia in rats. These exciting new data, together with our published studies showing
AIBP efficacy and mechanism of action in chemotherapy-induced peripheral neuropathy, suggest the potential
of AIBP (RFT1124) in treatment of postoperative pain. In Phase I of this Fast-Track STTR proposal, we will
define the efficacy of intravenous RFT1124 delivery on postoperative pain in rats, including: (i) dose response;
(ii) dependence on the time of pre or post incision administration; (iii) sex differences. In Phase II, we plan to
manufacture and release RFT1124 drug product for expanded efficacy and toxicology studies using cGMP-
compatible processes and analytical assays. Further, a pharmacokinetics of RFT1124 in blood and DRG and a
non-GLP safety assessment of intravenous delivery of RFT1124 will be conducted to establish an estimate of
safety margin and target organs. As an independent biomarker of activity, we will characterize the effects of
RFT1124 on hyperactivity in rat DRG neurons otherwise produced by surgical incision in male and female rats.
The efficacy studies will be extended to human DRG nociceptive neurons in culture, with the DRG obtained from
donors of both sexes. Target engagement will be tested with an AIBP variant, which like RFT1124 alters lipid
rafts but does not bind TLR4. We anticipate significant suppression of allodynic behavior and ectopic activity
induced by surgical injury after incision by RFT1124 but not the AIBP variant lacking the TLR4-binding domain.
These studies will provide the enabling data set to initiate a pre-IND meeting with the FDA in anticipation of
moving RFT1124 into first-in-human clinical trials.
CONFIDENTIAL
项目摘要
术后疼痛是一种普遍的疼痛来源,需要适当的管理,以减少其对患者的影响。
生活质量即使有几种止痛药,术后疼痛往往是用药不足
由于与可用治疗剂的不良后果相关的考虑(例如,NSAID和阿片类药物),
包括成瘾和癌症患者生存率下降。为此,我们已着手开发
RFT 1124,一种修饰的载脂蛋白A-I结合蛋白(AIBP),通过特异性靶向发挥作用
通过改变背根神经节(DRG)神经元局部膜胆固醇动力学来改变膜脂筏
和巨噬细胞以及表达TLR 4(TLR 4-筏)的脊髓小胶质细胞中,并且已知参与
处理继发于神经和组织损伤的急性和慢性疼痛。我们发现TLR 4-筏
在巨噬细胞上大量表达,并且仅在伤害性DRG神经元上表达。我们已经证明,
可能通过RFT 1124(AIBP)的作用特异性靶向这些TLR 4筏,RFT 1124(AIBP)结合TLR 4,
特异性地破坏相关的脂筏。AIBP在体外阻断人背根神经节伤害性感受器的异位活动
分离自疼痛的皮节。在体内,在爪切口之前静脉内注射AIBP防止了
大鼠触觉异常性疼痛的发展。这些令人兴奋的新数据,以及我们发表的研究表明,
AIBP在化疗诱导的周围神经病变中的疗效和作用机制,表明了其潜在的
AIBP(RFT 1124)治疗术后疼痛。在本快速通道STTR提案的第一阶段,我们将
定义静脉注射RFT 1124对大鼠术后疼痛的疗效,包括:(i)剂量反应;
(ii)对切口前或切口后给药时间的依赖性;(iii)性别差异。在第二阶段,我们计划
使用cGMP生产和放行用于扩展疗效和毒理学研究的RFT 1124制剂-
兼容的工艺和分析测定。此外,还研究了血液和DRG中RFT 1124的药代动力学,
将对静脉输注RFT 1124进行非GLP安全性评估,以确定
安全范围和靶器官。作为一个独立的生物标志物的活动,我们将表征的影响,
RFT 1124对雄性和雌性大鼠中由手术切口产生的大鼠DRG神经元活动过度的影响。
功效研究将扩展至培养的人DRG伤害感受神经元,其中DRG从
两种性别的捐赠者。将使用AIBP变体测试靶标接合,该变体与RFT 1124一样改变脂质
筏,但不结合TLR 4。我们预期异常性疼痛行为和异位活动的显著抑制
RFT 1124引起的手术损伤,但不是缺乏TLR 4结合结构域的AIBP变体。
这些研究将提供支持数据集,以启动与FDA的IND前会议,预计
将RFT 1124首次用于人体临床试验。
机密
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)
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Patrick M Dougherty其他文献
Patrick M Dougherty的其他文献
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{{ truncateString('Patrick M Dougherty', 18)}}的其他基金
Anatomic, Physiologic and Transcriptomic Mechanisms of Neuropathic Pain in Human DRG
人类背根神经节神经病理性疼痛的解剖学、生理学和转录组学机制
- 批准号:
10595036 - 财政年份:2020
- 资助金额:
$ 41.48万 - 项目类别:
Anatomic, Physiologic and Transcriptomic Mechanisms of Neuropathic Pain in Human DRG
人类背根神经节神经病理性疼痛的解剖学、生理学和转录组学机制
- 批准号:
10268154 - 财政年份:2020
- 资助金额:
$ 41.48万 - 项目类别:
Anatomic, Physiologic and Transcriptomic Mechanisms of Neuropathic Pain in Human DRG
人类背根神经节神经病理性疼痛的解剖学、生理学和转录组学机制
- 批准号:
10379957 - 财政年份:2020
- 资助金额:
$ 41.48万 - 项目类别:
The role of ENF loss, TLR4 and spinal plasticity in paclitaxel CIPN
ENF 缺失、TLR4 和脊柱可塑性在紫杉醇 CIPN 中的作用
- 批准号:
9271164 - 财政年份:2016
- 资助金额:
$ 41.48万 - 项目类别:
Mechanisms of Chemotherapy-Induced Peripheral Pain
化疗引起的周围疼痛的机制
- 批准号:
8475675 - 财政年份:2007
- 资助金额:
$ 41.48万 - 项目类别:
Mechanisms of Chemotherapy-Induced Peripheral Pain
化疗引起的周围疼痛的机制
- 批准号:
8640982 - 财政年份:2007
- 资助金额:
$ 41.48万 - 项目类别:
Mechanisms of Chemotherapy-Induced Peripheral Pain
化疗引起的周围疼痛的机制
- 批准号:
8401100 - 财政年份:2007
- 资助金额:
$ 41.48万 - 项目类别:
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