A novel PEDF peptide mimetic for diabetic retinopathy
一种治疗糖尿病视网膜病变的新型 PEDF 肽模拟物
基本信息
- 批准号:10483081
- 负责人:
- 金额:$ 54.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdoptionAftercareAmino AcidsAnimalsArtificial TearsBackBiological AssayBiological AvailabilityBiological ProductsBiomimeticsBlindnessBlood VesselsC-terminalCataractCell DeathChemicalsClinicalClinical TrialsComplications of Diabetes MellitusCorneaDevelopmentDiabetic NephropathyDiabetic RetinopathyDiseaseDoseEyeEyedropsFormulationFrequenciesGenderGeneticGlycoproteinsGoalsHumanIn VitroInflammationLabelLeadLegal patentLengthMAP Kinase GeneModelingModificationN-terminalOryctolagus cuniculusOutcomePathologyPathway interactionsPenetrationPeptidesPhasePhase I/II Clinical TrialPhase II Clinical TrialsPhylogenetic AnalysisPopulationPositioning AttributeProteinsResearchRetinaRetinal DegenerationRodentSafetySeriesSmall Business Technology Transfer ResearchStructureSymptomsTemperatureTestingTherapeuticTissuesToxic effectTreatment EfficacyVascular Endothelial Growth FactorsVisionVisualVisual AcuityWorkanalogbaseclinical developmentclinical translationclinically relevantcommercial applicationcostcost effective treatmentdiabeticdosagedrug efficacyimprovedin vivoin vivo Modelinjuredlead candidatemeetingsmimeticsmolecular modelingmouse modelnovelnovel therapeuticspeptide analogpeptidomimeticsphase 1 studyphase 2 studypigment epithelium-derived factorpigment epithelium-derived factor receptorpre-clinicalpreclinical studyprototypereceptorretinal prosthesissystemic toxicitytherapeutic proteintranslational approach
项目摘要
Abstract
The overall goal of Skyran Biologics is to develop a potent topical therapeutic for diabetic retinopathy (DR), a
leading cause of vision loss globally. Our research team identified Pigment Epithelium-Derived Factor (PEDF)
and showed it is expressed in the eye and provides significant protection to the injured retina. Since its discovery,
we identified a 44-mer N-terminus bioactive region of PEDF, then generated over 40 structurally different analogs
to this region. We screened these mimetics for biological activity in a set of rigorous in vitro and in vivo assays
for DR and identified Spx81-5 as a lead small PEDF mimetic with improved bioactivity in the DR retina over
the native 44-mer fragment. A chemically and reproducibly synthesized small bioactive peptide removes some
of the therapeutic challenges and cost encountered with a large glycoprotein in treating ocular diseases.
STTR Phase I Preclinical Summary: We extended previous studies showing that Spx81-5 reduces
inflammation, vascular pathologies, and cell death in DR to now show that topical instillations of Spx81-5
effectively improves visual acuity and contrast thresholds in diabetic rodents, activates MAPK through the
ATGL receptor, and is detected at therapeutic concentrations after a single low dose in rabbit retinas where
there is substantial back-to-front vitreal flow. We also show that Spx81-5 is stable at various temperatures for
>5 months and that a novel formulation FLP3 delivers ~70% more Spx81-5 to the retina than artificial tears.
Pre-clinical Phase II study: We propose to continue to develop Spx81-5 for DR and will use three aims to address
key scientific issues essential for filing an IND application: The first is to establish Dosage and Instillation
Frequency of Spx81-5 in a novel eye drop Formulation (FLP3) to achieve maximal therapeutic benefits in a
genetic mouse model (Ins2Akita) of DR. The second is to validate Bioavailability (PK) and Efficacy of Spx81-
5/FLP3 in Larger Rabbit Eyes with DR, and the third is to assess Safety and Tolerability of Spx81-5/FLP3 in
rabbit ocular and non-ocular tissues to allow prediction for human treatment.
Commercial Potential: Skyran Biologics Inc. can significantly increase clinical value of Spx81-5 by definitively
demonstrating that (i) the improved FLP3 topical vehicle enhances posterior segment delivery of the peptide, (ii)
topical instillations of Spx81-5/FLP3 restores visual function across multiple models of DR, and (iii) the peptide
is safe and tolerated in large animals. These studies are critical and essential to support the current regulatory
paradigm and to inform a pathway to human trials.
The milestones achieved by the successful completion of this work will position us to propose development of
GMP grade peptide and formulation for clinical translation. The Phase II work will move us towards essential
IND-enabling studies for FDA approval and development of clinical phase translational strategies.
摘要
Skyran Biologics的总体目标是开发一种有效的糖尿病视网膜病变(DR)局部治疗药物,
全球视力丧失的主要原因。我们的研究小组鉴定了色素上皮衍生因子(PEDF)
并显示它在眼睛中表达,并对受损的视网膜提供重要的保护。自从它被发现以来,
我们鉴定了PEDF的44-mer N-末端生物活性区,然后产生了40多种结构上不同的类似物
到这个地区。我们在一组严格的体外和体内试验中筛选了这些模拟物的生物活性
并将Spx 81 -5鉴定为在DR视网膜中具有改善的生物活性的领先小PEDF模拟物,
天然44聚体片段。化学和可重复合成的小生物活性肽去除了一些
大糖蛋白在治疗眼部疾病中遇到的治疗挑战和成本。
STTR I期临床前总结:我们扩展了先前的研究,表明Spx 81 -5降低了
DR中炎症、血管病变和细胞死亡现在显示Spx 81 -5的局部滴注
有效地改善糖尿病啮齿动物的视力和对比度阈值,
ATGL受体,并且在兔视网膜中单次低剂量后在治疗浓度下检测到,其中
存在大量的从后到前的玻璃体流动。我们还表明,Spx 81 -5在不同温度下是稳定的,
>5个月,并且新型制剂FLP 3向视网膜递送的Spx 81 -5比人工泪液多约70%。
临床前II期研究:我们建议继续开发用于DR的Spx 81 -5,并将使用三个目标来解决
提交IND申请的关键科学问题:首先是确定剂量和滴注
Spx 81 -5在新型滴眼剂制剂(FLP 3)中的频率,以在一种治疗中实现最大治疗益处。
第二个是验证Spx 81的生物利用度(PK)和功效。
第一是评估Spx 81 - 5/FLP 3在患有DR的较大兔眼中的安全性和耐受性,第二是评估Spx 81 -5/FLP 3在患有DR的较大兔眼中的安全性和耐受性。
兔眼和非眼组织,以允许预测人类治疗。
商业潜力:Skyran Biologics Inc.可以显著增加Spx 81 -5的临床价值,
证明(i)改进的FLP 3局部载体增强肽的后段递送,(ii)
局部滴注Spx 81 -5/FLP 3在多种DR模型中恢复视觉功能,和(iii)肽
在大型动物中安全且耐受。这些研究对于支持当前的监管政策至关重要。
范例,并为人类试验提供信息。
成功完成这项工作所取得的里程碑将使我们能够提出发展
GMP级肽和制剂用于临床翻译。第二阶段的工作将使我们朝着基本的方向发展,
为FDA批准和临床阶段转化策略的开发进行IND使能研究。
项目成果
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{{ truncateString('Ji-Ye Wei', 18)}}的其他基金
A novel PEDF peptide mimetic for diabetic retinopathy
一种治疗糖尿病视网膜病变的新型 PEDF 肽模拟物
- 批准号:
10680606 - 财政年份:2018
- 资助金额:
$ 54.23万 - 项目类别:
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