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.

我们对眼部微生物角膜炎中的宿主病原体相互作用一直很感兴趣 制定更好治疗策略的最终目标。严重的角膜炎是非常有害的 化学损伤的后遗症并导致视力障碍或暴露于硫后的损失 芥末酱是在战争中和ISIS等恐怖组织中使用的。 申请是对NOT-NS-20-030 FOA的响应，该FOA旨在补充现有的 奖励将研究扩展到开发对化学威胁的对策，包括 硫芥末酱暴露，并且符合我们希望将我们的工作扩展到化学的愿望 诱发角膜炎。 角膜血管化降低了透明度，并通过 促进各种免疫细胞的进入。因此，血管化是一种吸引人的疗法 治疗角膜炎的靶标。近年来，反VEGF生物制剂非常明显 成功治疗与年龄相关的黄斑变性和糖尿病性视网膜病， 自然，引起了使用这些试剂来管理角膜新血管形成的兴趣。这 困难的是，这些生物制剂（可溶性​​大分子）被洗净 分钟局部应用于眼睛时，几乎没有效率或没有效率。我们的解决方案是 将“锚”连接到生物学上，即结合角膜的结构域，因此 防止洗净。目前，我们正在使用小麦胚芽凝集素作为锚点，该锚与 在细胞表面和细胞外基质上非常丰富的GlcNAC和唾液酸。这 将停留时间从几分钟延长到至少24小时，我们以前有 每天仅使用一次锚定的生物学来显示在干眼模型中的效率。 这项研究的假设是使用锚定生物制剂靶向灭活VEGF可以 防止化学挑战的小鼠角膜中的新血管化。研究计划是1） 在生物化学上产生并验证小麦胚芽凝集素偶联的小鼠抗体 VEGF，2）测量锚定抗体对体内血管化的应用的影响 已建立的新血管形成模型，3）使用该程序来确定程度 锚定抗VEGF抗体可减少对氮的新血管化 芥末。该补充的长期目标是生成初步数据以进一步指导 工作并获得反对计划的赠款支持，以开发一种生物学来阻止 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