Investigation of urinary extracellular vesicles as novel and safe therapeutics for autosomal recessive polycystic kidney disease
尿细胞外囊泡作为常染色体隐性遗传性多囊肾病的新型安全疗法的研究
基本信息
- 批准号:10750704
- 负责人:
- 金额:$ 46.57万
- 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:2023-09-04 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAgeAmniotic FluidAutosomal Dominant Polycystic KidneyAutosomal Recessive Polycystic KidneyBindingBiodistributionBiologicalBirthCell CommunicationCellsCessation of lifeCharacteristicsChildhoodClinical TrialsDevelopmentDiseaseDisease ProgressionDoseDrug KineticsDrug Side EffectsEnd stage renal failureFDA approvedFetal LungFetusGeneticHalf-LifeHepatotoxicityHomeHourHumanIn VitroInjectionsIntravenousInvestigationKidneyKidney DiseasesKidney FailureKidney TransplantationLifeLive BirthMeasuresMembraneMessenger RNAModelingMothersMusMutateMutationNephrologyNewborn InfantOligohydramniosPKHD1 geneParentsPathway interactionsPatientsPharmaceutical PreparationsPhase I Clinical TrialsPilot ProjectsPolycystic Kidney DiseasesProliferatingPropertyProteinsPulmonary Valve InsufficiencyRNARattusReceptor Protein-Tyrosine KinasesRenal functionResearchRespirationSafetySourceTestingTherapeuticTherapeutic EffectToxic effectTranslatingTreatment EfficacyTyrosine Kinase InhibitorUrineVasopressin ReceptorWorkautosomebiomaterial compatibilitybody cavitycongenital hepatic fibrosiscpk mousedesigndisease phenotypeeffective therapyexosomeextracellular vesiclesfetalgene productgene therapyin uteroin vivoinhibitorinsightkidney celllung developmentmouse modelmultidisciplinarynanomedicinenanoparticleneonatenovelnovel strategiesnovel therapeutic interventionnovel therapeuticspatient populationpediatric patientspregnantprotein expressionpulmonary hypoplasiapupsmall moleculetargeted treatmenttherapeutic nanoparticlestherapy developmenttherapy outcometolvaptanurinary
项目摘要
ABSTRACT
Autosomal recessive polycystic kidney disease (ARPKD) is a leading cause of kidney failure in childhood and is
caused primarily by mutations in the PKHD1 gene as well as mutations in CYS1. Although ARPKD patients
progress to end stage kidney disease at varying ages, 20-30% of ARPKD patients have severe disease which
results in death 24-48 hours after birth. Despite the tremendous unmet need, limited progress has been made
for ARPKD treatment and no FDA-approved therapies are available for ARPKD patients. Although tolvaptan, a
small molecule drug that was approved in 2018 for autosomal dominant PKD which mostly affects adults, is
currently under phase I clinical trials for ARPKD, tolvaptan is not kidney-targeted and results in off-target effects.
Additionally, tolvaptan’s long-term efficacy, tolerability, and developmental consequences in a primarily pediatric
ARPKD patient population and its ability to enhance survival in neonates with severe ARPKD is unknown. Thus,
new therapeutic strategies that can address both safety and efficacy in ARPKD are urgently needed. To that
end, the purpose of this proposal is to examine the potential of urinary extracellular vesicles (uEVs) as a novel
and safe therapy for ARPKD. EVs, also known as exosomes, are secreted, membrane-bound, biological
nanoparticles that facilitate cell-to-cell communication and contain RNA and protein cargo characteristic to their
parent cell. We propose uEVs for ARPKD therapy for several reasons: uEVs are 1) inherently biocompatible
which is critically important when developing therapies for pediatric patients, 2) carry fibrocystin and cystin, the
gene products of PKHD1 and CYS1 which are mutated in ARPKD, respectively, 3) have been found to home to
the kidneys and transfer functional proteins to induce a therapeutic outcome in kidney disease, and 4) obtaining
high quantities uEV from urine, which is normally discarded, is feasible, noninvasive, and cheap. We hypothesize
that uEVs derived from non-disease sources are a safe therapy that can be used to deliver and supplement
functional proteins including fibrocystin and cystin that are defective in ARPKD to inhibit disease progression. To
test our hypothesis, we will first characterize the nanoparticle properties of uEVs and evaluate uEV fibrocystin
and cystin protein and mRNA cargo, cell internalization, and therapeutic effects in renal cells in vitro (Aim 1).
Next, we will administer uEVs intravenously in slowly progressing and severe ARPKD murine models and
evaluate the pharmacokinetic properties, therapeutic efficacy, and safety in vivo (Aim 2.1). Finally, given most
human ARPKD leads to death in utero or in newborns shortly after birth, we will deliver uEVs in utero in pregnant
mice and evaluate the ability to extend survival in severe ARPKD upon fetal delivery (Aim 2.2). Through our
multidisciplinary, investigative team of nanomedicine and pediatric nephrology, we are well-equipped and fully
committed to successfully carry out this work that is much needed in ARPKD therapy.
摘要
常染色体隐性遗传性多囊肾病(ARPKD)是儿童肾衰竭的主要原因,
主要由PKHD 1基因突变以及CYS 1突变引起。虽然ARPKD患者
在不同的年龄发展为终末期肾病,20-30%的ARPKD患者患有严重疾病,
导致出生后24-48小时死亡。尽管有巨大的未满足需求,但取得的进展有限
对于ARPKD治疗,没有FDA批准的疗法可用于ARPKD患者。虽然托伐普坦,
2018年批准用于常染色体显性PKD的小分子药物,主要影响成人,
目前处于ARPKD的I期临床试验中,托伐普坦不是肾靶向的,并导致脱靶效应。
此外,托伐普坦的长期疗效,耐受性和发育后果,主要是儿科
ARPKD患者人群及其提高重度ARPKD新生儿生存率的能力尚不清楚。因此,在本发明中,
迫切需要能够解决ARPKD的安全性和有效性的新的治疗策略。与
最后,本建议的目的是检查尿细胞外囊泡(uEVs)作为一种新的
和安全的治疗方法EV,也称为外泌体,是分泌的、膜结合的、生物相容的。
促进细胞间通讯并含有RNA和蛋白质货物特征的纳米颗粒,
母细胞。我们建议将uEV用于ARPKD治疗有几个原因:1)uEV具有固有的生物相容性
这在为儿科患者开发治疗方法时至关重要,2)携带纤维囊蛋白和囊蛋白,
分别在ARPKD中突变的PKHD 1和CYS 1的基因产物,3)已经发现归巢于
肾和转移功能蛋白以诱导肾病的治疗结果,和4)获得
从通常被丢弃的尿液中提取大量的uEV是可行的、非侵入性的和便宜的。我们假设
来自非疾病来源的uEV是一种安全的治疗方法,可用于提供和补充
在ARPKD中有缺陷的功能性蛋白质,包括纤维囊蛋白和囊蛋白,以抑制疾病进展。到
为了验证我们的假设,我们将首先描述uEV的纳米颗粒特性,并评估uEV纤维囊蛋白
以及cystin蛋白和mRNA货物、细胞内化和体外肾细胞中的治疗效果(目的1)。
接下来,我们将在缓慢进展和严重ARPKD小鼠模型中静脉注射uEV,
评价体内药代动力学特性、疗效和安全性(目标2.1)。最后,鉴于大多数
人ARPKD导致子宫内或出生后不久的新生儿死亡,我们将在妊娠期子宫内递送uEV。
小鼠,并评估在胎儿分娩时延长严重ARPKD存活的能力(目的2.2)。通过我们
多学科,纳米医学和儿科肾病学的研究团队,我们装备精良,
致力于成功开展ARPKD治疗中急需的这项工作。
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)
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Eun Ji Chung其他文献
Eun Ji Chung的其他文献
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{{ truncateString('Eun Ji Chung', 18)}}的其他基金
Multimodal Peptide Amphiphile Micelles for Atherosclerosis
用于治疗动脉粥样硬化的多模式肽两亲胶束
- 批准号:
9321402 - 财政年份:2015
- 资助金额:
$ 46.57万 - 项目类别:
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