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肽，BP 001，来自人类内源性宿主 防御蛋白CAP 37，作为一种新型的多靶点眼用产品，用于角膜感染和损伤。的 角膜感染的护理标准是局部施用抗生素， 类固醇，以限制由此产生的角膜炎症的破坏性作用。抗生素的功效有限 由于耐药细菌的惊人增加，类固醇的使用受到其潜在副作用的限制 （复发性感染，眼内压升高）。BP 001具有多种有益效果， 作为一种新产品来缓解这些限制。它是杀菌，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，促进角膜上皮再生，根据我们最近的研究结果， 预测其通过抑制Toll样受体而具有抗炎作用。有趣的是，我们最近观察到， 用于制备BP 001的缓冲液的组成极大地影响其体外杀菌性能。建筑 根据这一观察，我们在第一阶段申请中的具体目标是：1）开发和优化眼科 BP 001制剂增强对铜绿假单胞菌的有效杀灭，以及2）证明使用BP 001制剂的益处 BP 001单用和与氧氟沙星联合治疗细菌性角膜炎的优化制剂。 我们将使用设计质量（QbD）方法开发符合关键质量属性的制剂， 定义为（a）增强杀菌效力（与原始盐水溶液相比至少10倍，（B） 不会刺激眼睛，（c）增强溶液在眼睛中的保留，以使BP 001在眼睛中的作用最大化。 作用部位，和d）当组合使用时不干扰氧氟沙星的杀菌效力。 测量的结果将是粘度、最小杀菌浓度和BP 001和BP 002的协同效应。 在制剂中制备氧氟沙星并在铜绿假单胞菌的敏感和耐药菌株上进行测试。然后我们将 使用目的1中优化的制剂来评价BP 001体内杀菌活性的增强。我们将 进行BP 001和氧氟沙星在生理盐水和制剂中的剂量反应，以及 使用细菌性角膜炎的小鼠模型制备制剂中的BP 001/氧氟沙星组合治疗 由铜绿假单胞菌的耐药菌株诱导。在第一阶段结束时，我们预计将制定一个 增强BP 001杀菌作用并支持有效清除细菌性角膜炎诱导的 耐药铜绿假单胞菌分离株通过BP 001/氧氟沙星组合。在第二阶段，我们将展示伤口 在角膜炎和角膜擦伤的小鼠模型中，使用 在I期优化配方。该项目的完成将促进一类新药物的开发 对角膜感染和损伤具有多靶点作用。