Novel Ophthalmic Product for Corneal Infections and Injuries

用于治疗角膜感染和损伤的新型眼科产品

• 批准号: 10156366
• 负责人: Heloise. ANNE Pereira
• 金额: $ 25.66万
• 依托单位: BIOLYTX PHARMACEUTICALS CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156366
• 关键词: Address; Advanced Development; Adverse effects; Affect; Anti-Inflammatory Agents; Antibiotics; Antiinflammatory Effect; Antimicrobial Resistance; Bacterial Infections; Bacterial Model; Blindness; Buffers; Cations; Cicatrix; Cornea; Corneal Abrasion; Corneal Injury; Corneal Ulcer; Development; Dose; Epithelial; Eye; Eye Injuries; Fluoroquinolones; Formulation; Generations; Host Defense; Human; Immune; In Vitro; Infection; Inflammation; Injury; Keratitis; Measures; Methodology; Mission; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; National Institute of Allergy and Infectious Disease; Ofloxacin; Ophthalmic Solutions; Outcome Measure; Peptides; Perforation; Pharmacologic Substance; Phase; Physiologic Intraocular Pressure; Property; Proteins; Pseudomonas aeruginosa; Resistance; Resolution; Saline; Site; Small Business Technology Transfer Research; Steroids; Testing; Toll-like receptors; Topical application; Ulcer; Viscosity; Vision; antimicrobial; bacterial resistance; bactericide; base; cationic antimicrobial protein CAP 37; corneal epithelial wound healing; corneal epithelium; corneal regeneration; design; in vivo; innovation; mouse model; multi-drug resistant pathogen; multidrug-resistant Pseudomonas aeruginosa; novel; novel drug class; pathogen; peptide drug; phase 1 study; preservation; resistant strain; response; standard of care; wound healing

Biolytx Pharmaceuticals Corp. is developing a peptide, BP001, derived from the human endogenous host defense protein CAP37, as a novel multi-target ophthalmic product for corneal infections and injuries. The standard-of-care for corneal infections is topical administration of antibiotics that may be accompanied by topical steroids, to limit the destructive effect of the resulting corneal inflammation. The efficacy of antibiotics is limited by the alarming increase of resistant bacteria, and the use of steroids is limited by their potential adverse effects (recrudescent infection, increased intraocular pressure). BP001 has multiple beneficial effects and is developed as a new product to mitigate these limitations. It is bactericidal, restores the sensitivity of resistant Pseudomonas aeruginosa to fluoroquinolones, promotes corneal re-epithelialization, and based on our recent results, is predicted to be anti-inflammatory through inhibition of a toll-like receptor. Interestingly, we recently observed that the composition of the buffer used to prepare BP001 greatly affects its bactericidal properties in vitro. Building on this observation, our specific aims in this phase I application are to 1) develop and optimize an ophthalmic formulation of BP001 to potentiate the effective killing of P. aeruginosa, and 2) demonstrate the benefit of using the optimized formulation for treatment of bacterial keratitis with BP001 alone and in combination with ofloxacin. We will use the Quality by design (QbD) approach to develop a formulation that meets critical quality attributes, defined as (a) enhances the bactericidal potency (at least 10-fold compared to the original saline solution, (b) does not irritate the eye, (c) enhances retention of the solution in the eye to maximize the effect of BP001 at the site of action, and d) does not interfere with the bactericidal potency of ofloxacin when used in combination. Measured outcomes will be viscosity, minimum bactericidal concentrations, and synergistic effects of BP001 and ofloxacin prepared in formulations and tested on sensitive and resistant strains of P. aeruginosa. We will then use the formulation optimized in aim 1 to evaluate enhancement of BP001 bactericidal activity in vivo. We will conduct dose-responses of BP001 and ofloxacin in saline and formulation, and a dose-response of the BP001/ofloxacin combination treatment prepared in formulation, using a mouse model of bacterial keratitis induced by a resistant strain of P. aeruginosa. At the conclusion of phase I, we expect to have developed a formulation that enhances BP001 bactericidal effects and supports efficient clearing of bacterial keratitis induced by a resistant P. aeruginosa isolate by the BP001/ofloxacin combination. In phase II, we will demonstrate wound healing and anti-inflammatory effects of BP001, in mouse models of keratitis and corneal abrasion, using the formulation optimized in phase I. Completion of this project will advance the development of a new class of drug with multi-targeted effects for corneal infections and injuries.

Biolytx制药公司正在开发一种来自人类内源性宿主的多肽BP001 防御蛋白CAP37，作为一种新型的多靶点眼科产品，用于治疗角膜感染和损伤。这个 角膜感染的标准护理是局部使用抗生素，可能伴随着局部使用 类固醇，以限制由此产生的角膜炎症的破坏性影响。抗生素的疗效是有限的。 由于抗药性细菌的惊人增加，类固醇的使用受到其潜在不良影响的限制 (复发感染，眼压升高)。BP001具有多种有益效果，并被开发为 作为一种新产品来缓解这些限制。它具有杀菌作用，恢复耐药假单胞菌的敏感性 铜绿假单胞菌对氟喹诺酮类药物有促进角膜再上皮化的作用，根据我们最近的结果， 预计通过抑制Toll样受体发挥抗炎作用。有趣的是，我们最近观察到 制备BP001所用缓冲液的组成对其体外杀菌性能有很大影响。建房 根据这一观察，我们在这一阶段应用的具体目标是：1)开发和优化眼科 BP001的配方，以增强对铜绿假单胞菌的有效杀灭，以及2)证明使用 BP001单用及联合氧氟沙星治疗细菌性角膜炎的最佳处方 我们将使用设计质量(QBD)方法来开发满足关键质量属性的配方， 定义为：(A)增强杀菌能力(至少是原来生理盐水的10倍，(B) 不刺激眼睛，(C)增强溶液在眼睛中的滞留，以最大限度地发挥BP001在 作用部位，以及d)与氧氟沙星联合使用时不干扰氧氟沙星的杀菌效力。 测量结果将是粘度、最低杀菌浓度以及BP001和BP001的协同效应。 氧氟沙星在制剂中制备，并在敏感和耐药的铜绿假单胞菌菌株上进行测试。到时候我们会的 使用目标1中优化的配方来评价BP001体内杀菌活性的增强。我们会 BP001和氧氟沙星在生理盐水和制剂中的剂量反应，以及 BP001/氧氟沙星联合制剂制备小鼠细菌性角膜炎模型 由一株抗药性铜绿假单胞菌诱导。在第一阶段结束时，我们预计已经开发出一种 增强BP001杀菌效果并支持有效清除细菌性角膜炎的配方 由耐药铜绿假单胞菌BP001/氧氟沙星联合。在第二阶段，我们将展示伤口 BP001对小鼠角膜炎和角膜擦伤模型的愈合和抗炎作用 一期优化处方该项目的建成将推动新一类药物的开发 对角膜感染和损伤有多靶点作用。