NON-IRRITATING RETINOIDS FOR THE TREATMENT OF AGING

用于治疗衰老的无刺激性维A酸

• 批准号: 6882570
• 负责人: William Paul Purcell
• 金额: $ 86.94万
• 依托单位: MOLECULAR DESIGN INTERNATIONAL, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882570
• 关键词: SCID mouse; aging; biopsy; cell proliferation; clinical research; collagen; drug screening /evaluation; enzyme linked immunosorbent assay; extracellular matrix; histochemistry /cytochemistry; human subject; organ culture; protein degradation; retinoids; skin irritation /irritant; skin transplantation; topical drug application; wound healing

DESCRIPTION (provided by applicant): This application represents the Phase II version of SBIR grant R43 AR049621 entitled "Non-Irritating Retinoids for the Treatment of Aging Skin". Studies carried out prior to Phase I and during the Phase I portion of this project have demonstrated that a synthetic retinoid (identified as MDI-301) is as effective as all-trans retinoic acid (RA) in stimulating collagen repair in the dermis of mice (topically treated) and human skin (in organ culture) but, unlike RA, is non-irritating. We expect, therefore, that MDI-301 will ultimately provide a non-irritating alternative to RA for topical use in the prevention and treatment of aged/photoaged skin. In this Phase II application, we have identified a number of critical issues that need to be addressed as part of the development process of MDI-301. The three specific aims of this Phase II application identify the issues and our approach for addressing each of them. In Specific Aim I we will compare MDI-301 and RA for ability to stimulate extracellular matrix production and inhibit extracellular matrix degradation in human skin transplanted to severe-combined immunodeficient (scid) mice. As part of these studies, we will determine if treatment results in a histologically-evident improvement in the structure of the transplanted skin and determine if function (i.e., wound-healing capacity) is concomitantly improved in the treated skin. In Specific Aim II, MDI-301 and RA will be compared for their ability to modulate events in human skin that contribute to irritation. The information from theses studies will be used to help understand, at the cellular and molecular levels, why MDI-301 is non-irritating under conditions in which RA is irritating. Finally, in Specific Aim III, we will begin the safety evaluation of MDI-301 necessary to file an Investigational New Drug (IND) application with the FDA. The major goal of the Phase II effort is to develop MDI-301 to the point where we can attract a drug-development partner having the resources to obtain regulatory approvals (IND, clinical trials, NDA) and to market the drug effectively.

描述（由申请人提供）：本申请代表SBIR授权R43 AR 049621的II期版本，标题为“用于治疗老化皮肤的非刺激性维甲酸”。在该项目的I期之前和I期部分期间进行的研究表明，合成类维生素A（鉴定为MDI-301）在刺激小鼠（局部治疗）和人类皮肤（器官培养）真皮中的胶原修复方面与全反式维甲酸（RA）一样有效，但与RA不同，它无刺激性。因此，我们预计MDI-301最终将提供一种非刺激性的RA替代品，用于预防和治疗老化/光老化皮肤。在第二阶段的应用中，我们已经确定了一些关键问题，这些问题需要作为MDI-301开发过程的一部分加以解决。第二阶段申请的三个具体目标确定了问题以及我们解决每个问题的方法。在具体目标I中，我们将比较MDI-301和RA刺激细胞外基质产生和抑制细胞外基质降解的能力，在人皮肤移植到严重联合免疫缺陷（scid）小鼠。作为这些研究的一部分，我们将确定治疗是否导致移植皮肤结构的组织学明显改善，并确定功能（即，伤口愈合能力）在治疗的皮肤中也随之得到改善。在特定目标II中，将比较MDI-301和RA调节人体皮肤刺激事件的能力。这些研究的信息将用于帮助在细胞和分子水平上理解MDI-301在RA具有刺激性的条件下无刺激性的原因。最后，在特定目标III中，我们将开始MDI-301的安全性评价，这是向FDA提交研究性新药（IND）申请所必需的。第二阶段工作的主要目标是将MDI-301开发到我们可以吸引有资源获得监管批准（IND，临床试验，NDA）并有效销售药物的药物开发合作伙伴的程度。