Phase II: Anti-inflammatory and Anti-scarring Actions of Amniotic Membrane Extra

第二阶段：羊膜额外的抗炎和抗疤痕作用

• 批准号: 7903691
• 负责人: SCHEFFER CG TSENG
• 金额: $ 43.81万
• 依托单位: TISSUETECH, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903691
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Blood Vessels; Burn Units; Cicatrix; Clinical; Collagen; Complex; Cornea; Current Procedural Terminology Codes; Data; Disease; Drug Formulations; Epithelial; Figs - dietary; Gel; Grant; Herpesvirus 1; Hospitals; Hyaluronan; Hyaluronic Acid; In Vitro; Inflammation; Intensive Care; Keratitis; Lasers; Marketing; Medical; Medical Device; Medicare; Membrane; Modeling; Mus; Operating Rooms; Operative Surgical Procedures; Ophthalmology; Oryctolagus cuniculus; Paper; Patient Care; Patients; Phase; Photorefractive Keratectomy; Physicians' Offices; Powder dose form; Progress Reports; PubMed; Publishing; R43 grant; Relative (related person); Research Personnel; Site; Small Business Innovation Research Grant; Solutions; Surface; Therapeutic; Tissues; Transplantation; Vision; Wound Healing; base; clinical application; clinical efficacy; cost; inhibitor/antagonist; interest; novel; novel therapeutics; ocular surface; public health relevance; reconstruction

DESCRIPTION (provided by applicant): Over the past decade, there has been a surge of interest in amniotic membrane transplantation (AMT) for ocular surface reconstruction. A number of studies have shown that AMT using cryopreserved AM (AmnioGraft(R)) manufactured by Bio-Tissue, Inc., a subsidiary of TissueTech, Inc., is effective in facilitating epithelial wound healing and reducing stromal inflammation, scarring and formation of unwanted new blood vessels. To facilitate the ease of patient care and reduce the overall medical cost, we have obtained SBIR Phase I and II grants (R43/R44 EY014768) to develop a "sutureless" AM graft so that AMT can be performed in a physician's office or at the bedside of an Intensive Care and Burn Unit without bringing the patient to the operating room. As a result, we have successfully developed ProKera(R), which has received the FDA's 510(k) clearance as a type II medical device. In 2008, we have distributed more than 4,000 units in the U.S. market for treating patients inflicted with a number of sight-threatening corneal surface diseases characterized by poor wound healing, unwanted inflammation, and excessive scarring. We envisioned that AM's inherent anti-inflammatory and anti- scarring actions can further be deployed to treat ocular surface diseases unmanageable by AmnioGraft(R) or ProKera(R), and to any other body sites where inflammation and scarring are of great concern. We further speculated that one solution to the physical constraint of AmnioGraft(R) or ProKera(R) is to develop a gel formulation based on AM extracts (AME). Through SBIR Phase I grant support (R43 EY017497), we have successfully validated the key manufacturing steps of generating AME and its lyophilized powder (AMP), and compared the relative potency of using collagen or hyaluronic acid (HA) as a vehicle to deliver their anti-inflammatory and anti-scarring actions (Aim 1). In addition, we have biochemically purified and characterized one covalent complex (HC7HA) containing HA and heavy chains (HC) of inter-a-inhibitor (IaI) as the active component in AME responsible for most, if not all, anti-inflammatory and anti-scarring effects observed in AM stroma (Aim 2). In Phase II, we thus propose to validate the potency of purified HC7HA complex in exerting in vitro anti-inflammatory and anti-scarring actions, verify the consistency of manufacturing HC7HA complex regarding its biochemical composition and purity, and optimize the HA gel formulation containing HC7HA complex (Aim 1). In addition, we propose to demonstrate clinical efficacies of the aforementioned gel formulation containing HC7HA complex in exerting an anti-inflammatory action in a murine model of HSV1-induced necrotizing stromal keratitis, and an anti-scarring action in a rabbit model of excimer laser-assisted photorefractive keratectomy (PRK) (Aim 2). Successful completion of the above two Aims will allow us to gather sufficient and pertinent data for IDE/IND submission to the FDA so that we may begin to commercialize the first ophthalmic topical formulation and continue to build a pipeline of new therapeutics based on AME or purified HC7HA complex so that we may expand our market spaces not only in ophthalmology, but also in other medical and surgical subspecialties. PUBLIC HEALTH RELEVANCE: This application proposes to develop a novel pipeline of therapeutics based on anti-inflammatory and anti-angiogenic actions of amniotic membrane extract as well as its purified covalent complex containing hyaluronan and heavy chains of inter-a-inhibitor. Successful completion of our proposed studies in Phase II will allow us to gather sufficient and pertinent data for IDE/IND submission to the FDA so that we may begin to commercialize the first ophthalmic topical formulation and expand our market spaces not only in ophthalmology, but also in other medical and surgical subspecialties.

描述(申请人提供)：在过去的十年里，羊膜移植(AMT)用于眼表重建的兴趣激增。许多研究表明，使用TisseTech公司的子公司Bio-Organet公司生产的冷冻保存AM(AmnioGraft(R))进行的AMT在促进上皮伤口愈合和减少间质炎症、疤痕形成和不需要的新血管形成方面是有效的。为了简化患者护理并降低整体医疗成本，我们获得了SBIR第一阶段和第二阶段的拨款(R43/R44 EY014768)，以开发一种“无缝合”AM移植物，使AMT可以在医生的办公室或重症监护和烧伤病房的床边进行，而无需将患者带到手术室。因此，我们成功地开发了ProKera(R)，它已经获得了FDA的510(K)批准，是一种第二类医疗设备。2008年，我们在美国市场销售了4,000多台，用于治疗患有多种危及视力的角膜表面疾病的患者，这些疾病的特点是伤口愈合不良、不必要的炎症和过度疤痕。我们预计，AM固有的抗炎和抗疤痕作用可以进一步用于治疗AmnioGraft(R)或ProKera(R)无法控制的眼表疾病，以及炎症和疤痕严重的任何其他身体部位。我们进一步推测，解决AmnioGraft(R)或ProKera(R)的物理限制的一个解决方案是开发一种基于AM提取物(AME)的凝胶配方。通过SBIR第一阶段赠款支持(R43 EY017497)，我们成功地验证了生产AME及其冻干粉(AMP)的关键制造步骤，并比较了使用胶原或透明质酸(HA)作为载体传递其抗炎和抗瘢痕作用的相对效力(目标1)。此外，我们还进行了生化纯化，并鉴定了一种含有HA和IAI重链(HC)的共价复合体(HC7HA)，它是AME中的活性成分，对AM间质中观察到的抗炎和抗瘢痕作用(如果不是全部)起作用(目标2)。因此，在第二阶段，我们建议验证纯化的HC7HA复合体在体外发挥抗炎和抗瘢痕作用的效力，验证制造HC7HA复合体的生物化学组成和纯度的一致性，并优化含有HC7HA复合体的HA凝胶配方(目标1)。此外，我们建议展示上述含有HC7HA复合体的凝胶制剂在HSV1诱导的坏死性基质角膜炎小鼠模型中的抗炎作用以及在准分子激光辅助准分子激光屈光性角膜切削术(PRK)的兔模型中的抗瘢痕作用(AIM 2)。上述两个目标的成功完成将使我们能够为IDE/IND提交给FDA收集足够和相关的数据，以便我们可以开始将第一个眼科局部制剂商业化，并继续建立基于AME或纯化的HC7HA复合体的新疗法流水线，这样我们不仅可以扩大我们在眼科领域的市场空间，也可以扩大我们在其他内科和外科领域的市场空间。 与公共健康相关：本申请建议开发一种新的治疗流水线，基于羊膜提取物的抗炎和抗血管生成作用，以及其含有透明质酸和重链-α-抑制物的纯化共价复合体。成功完成我们在第二阶段的拟议研究将使我们能够收集足够和相关的数据，以便向FDA提交IDE/IND，以便我们可以开始将第一个眼科局部制剂商业化，并扩大我们的市场空间，不仅在眼科，而且在其他内科和外科专科。