NOT-NS-20-030: Use of anchored biologics to treat vesicant induced neovascularization

NOT-NS-20-030：使用锚定生物制剂治疗发泡剂诱导的新血管形成

• 批准号: 10228255
• 负责人: ROBERT M SHANKS
• 金额: $ 11.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228255
• 关键词: Adrenal Cortex Hormones; Age related macular degeneration; Anti-Inflammatory Agents; Antibodies; Award; Binding; Biochemical; Biological; Bioterrorism; Blinded; Blindness; Cataract; Cauterize; Cell surface; Cells; Chemical Injury; Chemicals; Chronic; Cornea; Corneal Neovascularization; Data; Diabetic Retinopathy; Drug Targeting; Effectiveness; Epithelial; Exposure to; Extracellular Matrix; Eye; FDA approved; Fright; Future; Glaucoma; Goals; Grant; Hour; Human; Immune; Inflammation; Keratitis; Laceration; Measurement; Measures; Mechlorethamine; Military Personnel; Modeling; Modern Medicine; Mus; Mustard Gas; Patients; Peptides; Pharmaceutical Preparations; Photophobia; Poisoning; Procedures; Reagent; Research; Residencies; Sialic Acids; Silver Nitrate; Technology; Tertiary Protein Structure; Testing; Time; Topical application; Treatment Protocols; Vascular Endothelial Growth Factors; Vascularization; Vesicants; Visual Acuity; Visual impairment; Wheat Germ Agglutinins; Work; antibody conjugate; base; bevacizumab; chemical threat; cytokine; effective therapy; experimental study; eye dryness; in vivo; in vivo Model; interest; macromolecule; microbial; neovascularization; ocular pain; ocular surface; pathogen; prevent; programs; response; side effect; therapeutic target; treatment strategy; weapons

We have a long-standing interest in host-pathogen interactions in ocular microbial keratitis with the ultimate goal of developing better treatment strategies. Severe keratitis is a very damaging sequela of chemical injuries and causes vision impairment or loss after exposure to sulfur mustard, which has been used in warfare and by terrorist organizations such as ISIS. This application is in response to the NOT-NS-20-030 FOA, which is directed to supplement existing awards to expand research into developing countermeasures to chemical threats including sulfur mustard exposure, and is in accord with our desire to expand our work to chemically- induced keratitis. Corneal vascularization reduces transparency and furthermore drives inflammation by facilitating entry of various immune cells. Vascularization is therefore an appealing therapeutic target for treating keratitis. Anti-VEGF biologics have in recent years been remarkably successful in treating wet age-related macular degeneration and diabetic retinopathy, which naturally has led to interest in using these reagents to manage corneal neovascularization. The difficulty is that these biologics, which are soluble macromolecules, are washed out within minutes when applied topically to the eye and therefore have little or no efficacy. Our solution is to attach an “anchor” to the biologic i.e. a domain that binds to the cornea and therefore prevents wash-out. Currently we are using wheat germ agglutinin an anchor, which binds to GlcNAc and sialic acid that are very abundant on cell surfaces and extracellular matrix. This prolongs the residency time from a few minutes to at least 24 hours, and we have previously shown efficacy in a dry eye model by applying an anchored biologic just once daily. The hypothesis of this study is that targeted inactivation of VEGF using anchored biologics can prevent neovascularization in chemically challenged mouse corneas. The research plan is to 1) produce and validate biochemically a wheat germ agglutinin-conjugated antibody to mouse VEGF, 2) measure effects of application of the anchored antibody on vascularization in vivo in an established model of neovascularization, and 3) use the procedure to determine the extent that anchored anti-VEGF antibodies reduces neovascularization in response to nitrogen mustard. The long-term goal of this supplement is to generate preliminary data to guide further work and to obtain grant support under the CounterACT program to develop a biologic to block VEGF for use in humans.

我们长期以来对眼部微生物角膜炎中宿主与病原体的相互作用感兴趣 制定更好的治疗策略的最终目标是非常具有破坏性的。 化学损伤的后遗症，接触硫后会导致视力损伤或丧失 芥末已被用于战争和伊斯兰国等恐怖组织。 申请是为了响应 NOT-NS-20-030 FOA，该法案旨在补充现有的 奖励扩大对化学威胁对策的研究，包括 硫芥暴露，符合我们将工作扩展到化学领域的愿望- 诱发角膜炎。 角膜血管化降低了透明度，并进一步通过以下方式引发炎症： 因此，促进各种免疫细胞的进入是一种有吸引力的治疗方法。 近年来，用于治疗角膜炎的抗 VEGF 生物制剂很少。 成功治疗湿性年龄相关性黄斑变性和糖尿病视网膜病变， 自然引起了人们对使用这些试剂来管理角膜新生血管的兴趣。 困难在于，这些生物制剂是可溶性​​大分子，会在 局部涂抹在眼睛上几分钟，因此效果很小或没有效果。 将“锚”附加到生物制品上，即与角膜结合的结构域，因此 目前，我们使用胚芽凝集素作为锚来防止小麦被冲走。 GlcNAc 和唾液酸在细胞表面和细胞外基质上非常丰富。 将驻留时间从几分钟延长到至少24小时，我们之前已经 通过每天一次应用锚定生物学，在干眼模型中显示出功效。 本研究的假设是，使用锚定生物制剂靶向灭活 VEGF 可以 防止受到化学攻击的小鼠角膜中的新生血管形成 该研究计划是 1) 生产并生物化学验证小麦胚芽凝集素缀合的小鼠抗体 VEGF，2) 测量应用锚定抗体对体内血管化的影响 已建立的新血管形成模型，以及 3) 使用该程序确定其程度 锚定的抗 VEGF 抗体可减少对氮的反应而产生的新血管形成 该补充品的长期目标是生成初步数据以进一步指导。 工作并获得 CounterACT 计划的拨款支持，以开发一种生物制剂来阻断 VEGF 用于人类。

项目成果

Release of Moxifloxacin From Corneal Collagen Shields.

莫西沙星从角膜胶原盾的释放。

• DOI: 10.1097/icl.0000000000000421
• 发表时间: 2018
• 期刊: Eye & contact lens
• 作者: Zhou,Siwei;Hunt,KristinM;Grewal,ArmanS;Brothers,KimberlyM;Dhaliwal,DeepinderK;Shanks,RobertMQ
• 通讯作者: Shanks,RobertMQ

Extending the use of biologics to mucous membranes by attachment of a binding domain.

• DOI: 10.1038/s42003-023-04801-6
• 发表时间: 2023-05-02
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Shanks, Robert M. Q.;Romanowski, Eric G.;Romanowski, John E.;Davoli, Katherine;McNamara, Nancy A.;Klarlund, Jes K.
• 通讯作者: Klarlund, Jes K.

Gene Acquisition by a Distinct Phyletic Group within Streptococcus pneumoniae Promotes Adhesion to the Ocular Epithelium.

• DOI: 10.1128/msphere.00213-17
• 发表时间: 2017-09
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Antic I;Brothers KM;Stolzer M;Lai H;Powell E;Eutsey R;Cuevas RA;Miao X;Kowalski RP;Shanks RMQ;Durand D;Hiller NL
• 通讯作者: Hiller NL

The Short-chain Fatty Acid Propionic Acid Activates the Rcs Stress Response System Partially through Inhibition of d-Alanine Racemase.

• DOI: 10.1128/msphere.00439-22
• 发表时间: 2023-02-21
• 期刊: mSphere
• 影响因子: 4.8