Injury-targeted decorin for systemic anti-fibrotic treatment

描述（由申请人提供）：损伤的修复主要是倾向于重建组织连续性，而不是恢复原始组织的结构。这一过程导致了瘢痕和纤维化，这是一个跨越所有器官系统疾病的主要医学问题。该应用侧重于一种化合物，该化合物已被证明在减少小鼠全身治疗疤痕方面非常有效。该化合物是一种损伤靶向形式的公认的抗疤痕蛋白，装饰素。建议优化靶向decorin，用于后续的临床前研究和临床试验。对将装饰素传递到损伤部位的伤口归巢肽进行结构功能研究，优化肽和融合蛋白的结构，用于损伤归巢应用。初步结果表明，截断形式的肽可能比原来的9-氨基酸肽更有效地提供有效载荷的伤害。这种多肽和其他多肽变体将被测试为一种最有效地将装饰素输送到伤口的化合物。由于附着在Decorin核心蛋白上的单个糖胺聚糖链的存在和结构的差异，在哺乳动物细胞中产生的Decorin具有异质性。这种异质性可能会在监管审批方面造成问题。有证据表明，抗疤痕活性可能不需要糖胺聚糖链，这激发了均质、不含糖胺聚糖的靶向decorin作为抗疤痕剂的体内试验。该系统的抗疤痕活性，其中伤口归巢肽和装饰素是共同管理，而不是共价连接到另一个，也将探讨。如果有效，联合给药系统将更简单，也可以很容易地适应于靶向其他损伤靶向药物。随后的结果将允许选择最有希望的靶向decorin化合物进行进一步的临床前研究。这些研究可能会导致一种新的全身治疗，可以限制损伤和炎症组织中纤维化引起的永久性损伤。

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.