Injury-targeted decorin for systemic anti-fibrotic treatment

用于全身抗纤维化治疗的损伤靶向核心蛋白聚糖

• 批准号: 8199150
• 负责人: ERKKI RUOSLAHTI
• 金额: $ 22.04万
• 依托单位: VASCULAR BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199150
• 关键词: Amino Acids; Animal Model; Animals; Chimeric Proteins; Chondroitin Sulfate Proteoglycan; Cicatrix; Clinic; Clinical Trials; Core Protein; Data; Disease; Drug Delivery Systems; Fibrosis; Glycosaminoglycans; Grant; Heterogeneity; Homing; In Vitro; Injury; Liver Cirrhosis; Mammalian Cell; Medical; Modeling; Mus; Mutate; Myocardial Infarction; Peptides; Phase; Process; Proteins; Proteoglycan; Recombinants; Signal Transduction; Site; Skin; Stroke; Structure; System; Systemic Therapy; Testing; Tissues; Toxic effect; Variant; Work; base; body system; decorin; immunogenicity; improved; in vivo; inhibitor/antagonist; injured; injury and repair; peptide structure; pre-clinical; preclinical study; prevent; restoration; tumor; vascular inflammation; wound

DESCRIPTION (provided by applicant): The repair of injuries is dominated by a tendency to re-establish tissue continuity rather than restoring the structure of the original tissue. This process results in scarring and fibrosis, which is a major medical problem spanning diseases in all organ systems. This application focuses on a compound that has been shown to be highly effective in reducing scarring as systemic therapy in mice. The compound is an injury- targeted form of the well-established anti-scarring protein, decorin. The proposal is to optimize the targeted decorin for subsequent pre-clinical studies and clinical trials. Structure function studies on the wound- homing peptide that delivers decorin to the sites of injury will be conducted to optimize the structure of the peptide and the fusion protein for injury-homing applications. Preliminary results suggest that a truncated form of the peptide may be even more effective than the original 9-amino acid peptide in delivering payload to injuries. This and other variants of the peptide will be tested to a compound most effective in delivering decorin to wounds. Decorin produced in mammalian cells heterogeneous because of variation in the presence and structure of the single glycosaminoglycan chain attached to the decorin core protein. This heterogeneity could cause problems in terms of regulatory approvals. There is evidence to the effect that the glycosaminoglycan chain may not be needed for the anti-scarring activity, motivating in vivo testing of homogeneous, glycosaminoglycan-free targeted decorin as an anti-scarring agent. The anti-scarring activity of system in which the wound-homing peptide and decorin are co-administered rather than covalently attached to one another, will also be explored. If active, the co-administration system would be simpler and could also be easily adapted to the targeting of other injury-targeted drugs. The ensuing results will allow the selection of the most promising targeted decorin compound for further preclinical studies. These studies may result in a new systemic treatment that can limit the permanent damage caused by fibrosis in injured and inflamed tissues. PUBLIC HEALTH RELEVANCE: Scarring (fibrosis) resulting from injury, inflammation and vascular problems is a major medical problem spanning diseases such as heart attack, stroke, liver cirrhosis and wounds because scarring prevents restoration of the original tissue. A natural inhibitor of scarring, decorin, inhibits scar formation in animal models. We have improved the activity of decorin by adding a homing signal that directs decorin to sites of injury, and propose here studies that will advance the targeted decorin toward the clinic.

描述(申请人提供)：损伤的修复以重建组织连续性的趋势为主，而不是恢复原始组织的结构。这一过程会导致瘢痕形成和纤维化，这是一个跨越所有器官系统疾病的主要医学问题。这项申请的重点是一种化合物，已被证明是高度有效的减少瘢痕作为系统治疗小鼠。该化合物是一种针对损伤的抗疤痕蛋白核心蛋白。该提案旨在为后续的临床前研究和临床试验优化靶向Decorin。将对将核心蛋白聚糖输送到损伤部位的创伤归巢多肽进行结构功能研究，以优化多肽和融合蛋白的结构，用于损伤归巢应用。初步结果表明，截短形式的多肽可能比原始的9氨基酸多肽在运送有效载荷方面更有效。这种多肽和其他多肽的变种将被测试为一种最有效地将核心蛋白输送到伤口上的化合物。核心蛋白聚糖在哺乳动物细胞中产生的异质性是由于连接到核心蛋白核心蛋白上的单一糖胺多聚糖链的存在和结构的变化。这种异质性可能会在监管审批方面造成问题。有证据表明，糖胺多糖链可能不是抗瘢痕活性所必需的，这促使体内测试均一的、不含糖胺多糖的靶向核心蛋白作为抗瘢痕药物。还将探索伤口归巢多肽和核心蛋白聚糖共同给药而不是相互共价连接的系统的抗瘢痕活性。如果有效，联合给药系统将更简单，也可以很容易地适应其他针对伤害的药物的靶向。随后的结果将使我们能够选择最有前景的目标核心蛋白聚糖化合物进行进一步的临床前研究。这些研究可能导致一种新的全身性治疗方法，可以限制损伤和炎症组织中的纤维化造成的永久性损害。 与公共卫生相关：创伤、炎症和血管问题导致的瘢痕形成(纤维化)是一个主要的医学问题，涉及心脏病发作、中风、肝硬变和伤口等疾病，因为疤痕阻止原始组织的恢复。一种天然的疤痕形成抑制剂，核心蛋白聚糖，在动物模型中抑制瘢痕形成。我们已经通过增加引导核心蛋白聚糖到损伤部位的定位信号来提高核心蛋白聚糖的活性，并在这里提出了将靶向核心蛋白蛋白推向临床的研究。