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 Pharmaceuticals Corp.正在开发源自人内源宿主的肽BP001 防御蛋白CAP37，是一种用于角膜感染和损伤的新型多目标眼科产物。这 角膜感染的标准护理是局部给药抗生素，可能伴有局部 类固醇，以限制由此产生的角膜炎症的破坏作用。抗生素的功效有限 由于耐药细菌的惊人增加，并且使用类固醇受到潜在的不良反应的限制 （重新感染，眼内压）。 BP001具有多种有益的效果，并已开发 作为减轻这些限制的新产品。它是杀菌性的，可恢复抗性假单胞菌的灵敏度 铜绿去到氟喹诺酮类，促进角膜重新上皮化，并根据我们最近的结果是 预计通过抑制Toll样受体被预测为抗炎。有趣的是，我们最近观察到 用于制备BP001的缓冲液组成在体外极大地影响其杀菌特性。建筑 在此观察结果上，我们在I阶段I应用中的具体目标是1）开发和优化眼科 BP001的配方以增强有效杀死铜绿假单胞菌，2）证明了使用的好处 单独使用BP001并与氧氟沙星联合治疗细菌性角膜炎的优化配方。 我们将使用设计（QBD）方法的质量来开发符合关键质量属性的公式， 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）增强溶液在眼中的保留，以最大化BP001在 组合使用时，作用部位和d）不会干扰氧氟沙星的杀菌效力。 测得的结果将是粘度，最低杀菌浓度以及BP001和 在制剂中制备的氧氟沙星，并在铜绿假单胞菌的敏感和抗性菌株上进行了测试。然后我们会 使用AIM 1中优化的公式来评估体内BP001杀菌活性的增强。我们将 在盐水和配方中进行BP001和Ofloxacin的剂量反应，以及对剂量反应的剂量反应 BP001/在制剂中制备的loxacin组合治疗，使用细菌性角膜炎的小鼠模型 由铜绿假单胞菌的抗性菌株诱导。在第一阶段结束时，我们希望已经开发 增强BP001杀菌作用并支持细菌性角膜炎诱导的有效清除的配方 通过BP001/ofloxacin组合的抗性铜绿假单胞菌分离。在第二阶段，我们将证明伤口 BP001的愈合和抗炎作用，在角膜炎和角膜磨损的小鼠模型中 在第一阶段优化的配方。该项目的完成将推动开发新的药物 具有针对角膜感染和伤害的多靶向作用。