Development of Filociclovir for the Treatment of Ocular Adenoviral Infections and Keratoconjunctivitis
用于治疗眼部腺病毒感染和角结膜炎的非洛昔洛韦的开发
基本信息
- 批准号:10257718
- 负责人:
- 金额:$ 74.95万
- 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:2021-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcuteAdenovirus InfectionsAdenovirusesAdverse effectsAntiviral AgentsAreaArtificial TearsAustraliaBehavioralBiodistributionBiological AssayBlindnessCanis familiarisCardiovascular systemChemistryChronicCidofovirClinicalClinical ResearchClinical TrialsConjunctivitisCorneaCytomegalovirusCytomegalovirus InfectionsDataDevelopmentDiseaseDoseDrug KineticsEnzymesEpidemic KeratoconjunctivitisExcipientsExhibitsExperimental DesignsEyeEye InfectionsEyedropsFDA approvedFormulationFrequenciesGelGoalsHerpesviridae InfectionsHumanIn VitroIndiaInfectionInvestigational DrugsKeratitisKeratoconjunctivitisMedicalModelingMutationNational Eye InstituteNeurologicNo-Observed-Adverse-Effect LevelNon-Steroidal Anti-Inflammatory AgentsOrgan TransplantationOryctolagus cuniculusPancreatic ribonucleasePathologyPatientsPharmacologyPharmacology and ToxicologyPharmacotherapyPhasePhase I Clinical TrialsPhase II Clinical TrialsPhosphotransferasesPhototoxicityPolymerasePositioning AttributePovidone-IodinePrimary Care PhysicianRattusReactionRegimenResearch DesignResearch MethodologyResearch PriorityRouteSafetySchoolsSmall Business Innovation Research GrantSolidSupportive careTherapeuticTimeTopical CorticosteroidsToxic effectToxicokineticsToxicologyTransplant RecipientsUnited StatesViralViral Load resultVirus SheddingVisitVisualWorkcarcinogenicityconjunctivadosageeffective therapyefficacy studyexperimental studygenotoxicityinhibitor/antagonistnovelnucleoside analogophthalmic drugphase 2 studypre-clinicalpreclinical developmentpreclinical studyranpirnaserespiratorysafety studysocioeconomicssymptomatic improvement
项目摘要
Project Summary/Abstract
The long-term goal of this project, to develop filociclovir (FCV) for the safe and effective treatment of human
ocular adenovirus (AdV) infections, especially AdV-related epidemic keratoconjunctivitis (EKC), a stated National
Eye Institute (NEI) research priority. There are currently no treatments for patients suffering from adenoviral
conjunctivitis, which is responsible for up to 3.5 million lost school days and 8.5 million lost work days every year
in the U.S., or EKC, the most severe form of ocular adenoviral infection, which often causes long-term visual
sequelae, such as chronic keratitis and vision loss. As FCV has previously completed Phase 1 clinical studies
for a systemic indication of cytomegalovirus (CMV) infection in solid organ transplant recipients and is a potent
inhibitor of human adenoviruses, the objective of this SBIR proposal is to generate the remaining ocular-specific
preclinical (PC) data needed to support an investigational new drug (IND) submission to treat human ocular AdV
infections. In this Phase II SBIR, IND-enabling PC ocular pharmacokinetics (PK), biodistribution and GLP-
toxicology studies will be completed, along with confirmatory efficacy parameters, suitable for IND submission.
Additionally, we will confirm the mechanism of action of FCV against AdV and compare it with what is known for
the viral targets in CMV. The specific aims of this proposal, along with the research design and methods, are as
follows:
AIM 1. Optimize eye drop formulation with suitable excipients and confirm efficacy in the rabbit AdV
infection model (years 1-2). Milestones: Identify final formulation suitable for PC and human clinical ocular
safety and efficacy studies. Select most favorable dose level, frequency and duration. Experimental design:
formulation development, repeat Ad5/NZW rabbit eye infection model, dosage optimization in the same model.
AIM 2. Perform IND-enabling ocular biodistribution, systemic toxicokinetics, local dose range finding
ocular tolerance and repeat-dose ocular toxicology and supporting studies in albino rabbits and dogs
(years 1-2). Milestones: Determine ocular and systemic exposure and distribution to predict areas of potential
toxicity. Establish NOAEL to determine human clinical starting dose. Completion of acute local tolerance studies,
GLP 28-day subacute ocular toxicology and in vitro phototoxicity studies to support an IND filing. Experimental
design: complete remaining preclinical studies for the ocular route to support IND for ophthalmic product.
AIM 3. Conduct mechanism of action studies (years 1-2). Milestones: Confirm viral and host polymerase and
kinase targets. Experimental design: determine whether the mechanism of action identified for CMV is the same
for AdV by performing mutation experiments.
项目总结/摘要
该项目的长期目标是开发安全有效的治疗人类非昔洛韦(FCV),
眼腺病毒(AdV)感染,特别是AdV相关的流行性角膜结膜炎(EKC),
眼科研究所(NEI)研究优先。目前没有治疗患有腺病毒感染的患者的方法。
结膜炎,每年造成多达350万个上学日和850万个工作日的损失
在美国,或EKC,最严重的眼部腺病毒感染形式,通常会导致长期视力下降,
后遗症,如慢性角膜炎和视力下降。由于FCV此前已完成I期临床研究,
用于实体器官移植受者中巨细胞病毒(CMV)感染的全身适应症,
人腺病毒的抑制剂,这个SBIR建议的目的是产生剩余的眼部特异性
临床前(PC)数据,用于支持治疗人眼AdV的研究性新药(IND)申请
感染.在这项II期SBIR中,IND使能PC眼部药代动力学(PK)、生物分布和GLP-
将完成毒理学研究,沿着确证性有效性参数,适用于IND提交。
此外,我们将确认FCV对AdV的作用机制,并将其与已知的
CMV中的病毒靶点。本提案的具体目标,连同研究设计和方法,沿着如下
如下所示:
AIM 1.使用合适的辅料优化滴眼液处方,并确认在兔AdV中的有效性
感染模型(1-2年)。关键:确定适用于PC和人类临床眼部的最终制剂
安全性和有效性研究。选择最有利的剂量水平、频率和持续时间。实验设计:
制剂开发、重复Ad 5/NZW兔眼感染模型、在相同模型中剂量优化。
AIM 2.进行IND启用眼部生物分布、全身毒代动力学、局部剂量范围确定
白化病兔和犬的眼部耐受性和重复给药眼部毒理学及支持性研究
(1-2年级)。Milestone:确定眼部和全身暴露和分布,以预测潜在的区域
毒性确定NOAEL以确定人体临床起始剂量。完成急性局部耐受性研究,
GLP 28天亚急性眼部毒理学和体外光毒性研究,以支持IND申报。实验
设计:完成眼部途径的剩余临床前研究,以支持眼科产品的IND。
AIM 3.开展作用机制研究(1-2年级)。Milestone:确认病毒和宿主聚合酶,
激酶靶点。实验设计:确定确定CMV的作用机制是否相同
进行突变实验。
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 }}
Terry L. Bowlin其他文献
Investigating emN/em-arylpyrimidinamine (NAPA) compounds as early-stage inhibitors against human cytomegalovirus
调查 emN/em-芳基嘧啶胺(NAPA)化合物作为针对人类巨细胞病毒的早期抑制剂
- DOI:
10.1016/j.antiviral.2022.105474 - 发表时间:
2023-01-01 - 期刊:
- 影响因子:4.000
- 作者:
Andrea J. Parsons;Sabrina I. Ophir;Thomas J. Gardner;Jailene Casado Paredes;Kathryn R. Stein;Steven M. Kwasny;Steven C. Cardinale;Matthew Torhan;Mark N. Prichard;Scott H. James;Kristina E. Atanasoff;Narendran G-Dayanandan;Terry L. Bowlin;Timothy J. Opperman;Domenico Tortorella - 通讯作者:
Domenico Tortorella
The immune response to a chemically induced fibrosarcoma
- DOI:
10.1007/bf00200197 - 发表时间:
1982-06-01 - 期刊:
- 影响因子:5.100
- 作者:
Terry L. Bowlin;Max R. Proffitt - 通讯作者:
Max R. Proffitt
Adenosine A3 receptor agonists inhibit macrophage tumor necrosis factor‐α production
腺苷 A3 受体激动剂抑制巨噬细胞肿瘤坏死因子-α 的产生
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:0
- 作者:
Terry L. Bowlin;David R. Borcherding;C. K. Edwards;C. McWhinney - 通讯作者:
C. McWhinney
Inhibiteurs de la transformation de glycoprotéine ayant une activité antirétrovirale
糖蛋白转化抑制剂具有抗逆转录病毒活性
- DOI:
- 发表时间:
1988 - 期刊:
- 影响因子:0
- 作者:
S. P. Sunkara;Terry L. Bowlin;Paul S. Liu - 通讯作者:
Paul S. Liu
Methylacetylenic putrescine (MAP), an inhibitor of polyamine biosynthesis, prevents the development of collagen-induced arthritis.
甲基乙炔腐胺 (MAP) 是一种多胺生物合成抑制剂,可预防胶原诱导的关节炎的发生。
- DOI:
10.1016/0008-8749(90)90102-w - 发表时间:
1990 - 期刊:
- 影响因子:4.3
- 作者:
J. Wolos;Deborah E. Logan;Terry L. Bowlin - 通讯作者:
Terry L. Bowlin
Terry L. Bowlin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 }}
{{ truncateString('Terry L. Bowlin', 18)}}的其他基金
Development of Filociclovir for the Treatment of Ocular Adenoviral Infections and Keratoconjunctivitis
用于治疗眼部腺病毒感染和角结膜炎的非洛昔洛韦的开发
- 批准号:
10410533 - 财政年份:2021
- 资助金额:
$ 74.95万 - 项目类别:
Discovery of Zika virus therapeutics using a replicon assay
使用复制子测定发现寨卡病毒疗法
- 批准号:
9761977 - 财政年份:2018
- 资助金额:
$ 74.95万 - 项目类别:
Norovirus 3CL Protease-Based Anti-norovirus Therapeutics
基于诺如病毒 3CL 蛋白酶的抗诺如病毒疗法
- 批准号:
8615065 - 财政年份:2014
- 资助金额:
$ 74.95万 - 项目类别:
Novel Inhibitors Targeting Early Steps of Human Cytomegalovirus Replication
针对人类巨细胞病毒复制早期步骤的新型抑制剂
- 批准号:
8847279 - 财政年份:2014
- 资助金额:
$ 74.95万 - 项目类别:
Norovirus 3CL Protease-Based Anti-norovirus Therapeutics
基于诺如病毒 3CL 蛋白酶的抗诺如病毒疗法
- 批准号:
8793096 - 财政年份:2014
- 资助金额:
$ 74.95万 - 项目类别:
Evaluation of a new class of antimicrobial agents against Clostridium difficile
新型艰难梭菌抗菌药物的评价
- 批准号:
8337880 - 财政年份:2011
- 资助金额:
$ 74.95万 - 项目类别:
相似海外基金
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 74.95万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
- 批准号:
2244994 - 财政年份:2023
- 资助金额:
$ 74.95万 - 项目类别:
Standard Grant