Cell-Based, Chronic Wound Gene Therapy for Older Adults

描述(申请人提供)：根据创伤修复协会的数据，在美国，大约15%的老年人患有慢性、难以愈合的皮肤伤口。蛋白分解活性的增加与固有的皮肤老化有关，这容易使老年人的组织崩溃。此外，慢性创面本身就表现出高度的蛋白质分解环境，导致细胞外基质、关键的可溶性或基质相关的生长因子及其各自的细胞受体的异常降解。因此，老化皮肤的蛋白质分解特性不仅导致急性伤口愈合受损，而且使老年人现有的慢性皮肤伤口永久化。减轻慢性伤口高度蛋白质分解环境的策略有可能极大地促进这些难以愈合的伤口的愈合。 到目前为止，还没有专门针对慢性伤口的蛋白质分解性质的生物治疗选择被开发和销售。在这个第一阶段的可行性确定中，我们建议建立和鉴定一种基因修饰的人角质形成细胞系，以结构性地表达一种功能性的、生物活性的蛋白酶抑制物。这种细胞试剂最终用于ExpressGraft(Tm)shieid，这是一种基于细胞的基因治疗产品，旨在对抗与老年人慢性皮肤伤口相关的过度蛋白质分解活动。Stratech公司在体外对获得专利的人类角质形成细胞系进行基因工程的进展使其具有完成这项工作的独特地位。在成功完成第一阶段目标后，我们将扩大我们的研究范围，在随后的第二阶段临床前测试中检查从候选细胞试剂在体外和体内产生的组织。

DESCRIPTION (provided by applicant): According to the Wound Healing Society, about 15% of older adults in the United States suffer from chronic, hard-to-heal skin wounds. An increase in proteolytic activity is associated with intrinsic cutaneous aging predisposing the elderly to tissue breakdown. Furthermore, chronic wounds inherently exhibit a highly proteolytic environment resulting in abnormal degradation of the extracellular matrix, critical soluble or matrix-associated growth factors, and their respective cellular receptors. Therefore, the proteolytic nature of aged skin not only contributes to impaired acute wound healing, but perpetuates existing chronic cutaneous wounds in older adults. Strategies to attenuate the highly proteolytic environment of chronic wounds have the potential to dramatically enhance the healing of these hard-to-heal wounds. To date no biological treatment options specifically targeting the proteolytic nature of chronic wounds have been developed and marketed. In this Phase I feasibility determination, we propose to generate and characterize a human keratinocyte cell line genetically-modified to constitutively express a functional, bioactive proteinase inhibitor. This cellular reagent is intended for eventual use in ExpressGraft(tm)shieid, a cell-based gene therapy product engineered to combat the excess proteolytic activity associated with chronic cutaneous wounds in the elderly. Advances in ex vivo genetic engineering of a patented human keratinocyte cell line at Stratatech Corporation has made it uniquely positioned to complete this work. Upon successful completion of Phase I objectives, we will expand our studies to examine tissue generated from candidate cellular reagents both in vitro and in vivo during subsequent Phase II preclinical testing.