Injury-targeted decorin for systemic anti-fibrotic treatment

描述（由申请人提供）：损伤的修复主要是重建组织连续性，而不是恢复原始组织的结构。这一过程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。本申请集中于一种化合物，该化合物已被证明作为小鼠的全身治疗在减少瘢痕形成方面非常有效。该化合物是公认的抗瘢痕蛋白核心蛋白聚糖的损伤靶向形式。该提案旨在优化靶向核心蛋白聚糖，用于后续的临床前研究和临床试验。将对将核心蛋白聚糖递送至损伤位点的伤口归巢肽进行结构功能研究，以优化用于损伤归巢应用的肽和融合蛋白的结构。初步结果表明，截短形式的肽可能比原始的9-氨基酸肽在向损伤递送有效载荷方面更有效。该肽的这种变体和其他变体将被测试为最有效地将核心蛋白聚糖递送到伤口的化合物。核心蛋白聚糖在哺乳动物细胞中的产生是异质的，这是由于与核心蛋白聚糖核心蛋白连接的单个糖胺聚糖链的存在和结构的变化。这种异质性可能会导致监管批准方面的问题。有证据表明，抗瘢痕形成活性可能不需要糖胺聚糖链，从而激发了均匀的、不含糖胺聚糖的靶向核心蛋白聚糖作为抗瘢痕形成剂的体内测试。还将探索其中伤口归巢肽和核心蛋白聚糖共施用而不是彼此共价连接的系统的抗瘢痕形成活性。如果有活性，联合给药系统将更简单，也可以很容易地适应其他损伤靶向药物的靶向。随后的结果将允许选择最有前途的靶向核心蛋白聚糖化合物进行进一步的临床前研究。这些研究可能会产生一种新的全身治疗方法，可以限制损伤和炎症组织中纤维化引起的永久性损伤。 公共卫生相关性：由损伤、炎症和血管问题引起的瘢痕形成（纤维化）是跨越诸如心脏病发作、中风、肝硬化和伤口的疾病的主要医学问题，因为瘢痕形成阻止原始组织的恢复。一种天然的瘢痕形成抑制剂，核心蛋白聚糖，在动物模型中抑制瘢痕形成。我们通过添加引导核心蛋白聚糖到损伤部位的归巢信号来提高核心蛋白聚糖的活性，并在此提出将靶向核心蛋白聚糖推向临床的研究。

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.