TGF-beta Antagonists for Accelerating Wound Healing

描述（由申请人提供）：在美国，每年有1250万人遭受烧伤，650万人因压力、静脉淤积或糖尿病而患有慢性皮肤溃疡，25万人患有严重到需要手术治疗的瘢痕瘤。在美国，烧伤治疗每年花费18亿美元。在美国，治疗慢性皮肤溃疡每年要花费130亿美元。在美国，糖尿病周围神经病变和/或神经性足溃疡的年度成本为1型糖尿病患者为8亿美元，2型糖尿病患者为101亿美元。保留肢体的外科手术也被广泛使用。尽管糖尿病足溃疡的护理和治疗花费巨大，但由于目前的治疗方法不是很有效，美国每年仍有82000例糖尿病足溃疡患者接受截肢手术。在美国，这些手术治疗每年花费约3亿美元。目前，还没有一种药物被证明对治疗皮肤伤口有效。正如这些成本所表明的那样，迫切需要开发有效的药物来加速伤口愈合，减少烧伤、爆炸伤、慢性皮肤溃疡、瘢痕疙瘩和其他类似疾病患者的疤痕或组织纤维化。治疗这些患者的新产品将推动市场。越来越多的证据表明，TGF-2作为一种细胞因子，为开发包括慢性伤口在内的多种类型伤口的新型治疗药物提供了理想的靶点。TGF-2在伤口部位产生，负责将炎症细胞和成纤维细胞募集到伤口部位，抑制上皮细胞生长（伤口再上皮化）并刺激伤口部位成纤维细胞合成细胞外基质（纤维化）。在之前的研究中，我们开发了一种合成的TGF-2肽拮抗剂（称为TGF-2肽拮抗剂），这是唯一已知的合成TGF-2受体拮抗剂。TGF-2肽拮抗剂可以促进猪皮肤烧伤/切除和兔皮肤切除伤口模型的伤口愈合和减少疤痕。然而，合成的TGF-2肽拮抗剂的有效性受到其在水溶液中的溶解度差的限制。该项目旨在开发新的化学形式的TGF-2肽拮抗剂，具有良好的溶解度，高组织渗透能力和有效的TGF-2拮抗剂活性，作为治疗人类伤口的候选药物。在I期研究中，我们开发了两种新的TGF-2肽拮抗剂，它们具有合理的工程特性，在水溶液中具有高溶解度，并且在体外抑制TGF-2活性方面比原型（未经修饰的）TGF-2肽拮抗剂强10倍。在几种动物损伤模型中，这两种新的TGF-2肽拮抗剂中的一种已被证明能有效地预防组织损伤，加速伤口愈合并减少疤痕。这些有希望的结果为第二期计划的拟议研究提供了依据。我们希望这两种新型TGF-2肽拮抗剂的临床可用性将被大型制药公司商业化，最终直接受益于包括正常，受损和慢性伤口在内的各种类型伤口的个体。

DESCRIPTION (provided by applicant): Every year in the United States, >1.25 million people suffer from burns, 6.5 million have chronic skin ulcers caused by pressure, venous stasis or diabetes mellitus and 0.25 million have keloids sufficiently severe to require surgery. Burn treatment costs $1.8 billion per year in the US. The treatment of persons with chronic skin ulcers costs $13 billion per year in the US. The annual cost of diabetic peripheral neuropathy and/or neuropathic foot ulcers in the U.S. is $ 0.8 billion for type I diabetics and $10.1 billion for type II diabetics. Limb-sparing surgical procedures are also widely used. In spite of these large costs for the care and the treatment of diabetic foot ulcers, each year 82,000 limb amputations are still performed on US patients with diabetic ulcers because current therapy is not very effective. These surgical treatments cost about $ 0.3 billion per year in the US. Currently, there is no agent which has been shown to be effective for treating cutaneous wounds. As these costs suggest, there is an urgent need for developing effective agents to accelerate wound healing and reduce scarring or tissue fibrosis in patients with burn injuries, blast injuries, chronic skin ulcers, keloids and other similar disorders. New products to treat these patients will drive the market. Accumulating evidence indicates that TGF-2, a cytokine, provides an ideal target for developing novel therapeutic agents for many types of wounds including chronic wounds. TGF-2 is produced at the wound site and is responsible for recruiting inflammatory cells and fibroblasts to the wound site, inhibiting epithelial cell growth (wound re-epithelialization) and stimulating extracellular matrix synthesis by fibroblasts (fibrosis) at the wound site. In prior studies, we developed a synthetic TGF-2 peptide antagonist (termed TGF-2 peptantagonist) which is the only known synthetic TGF-2 receptor antagonist. TGF-2 peptantagonist can enhance wound healing and reduce scarring in pig skin burn/excision and rabbit skin excision wound models. However, the efficacy of the synthetic TGF-2 peptantagonist is limited by its poor solubility in aqueous solution. This project aims at developing new chemical forms of our TGF-2 peptantagonist with excellent solubility, high tissue penetration ability and potent TGF-2 antagonist activity as drug candidates for treating wounds in humans. In Phase I studies, we have developed two new TGF-2 peptantagonists with rationally engineered properties exhibit high solubility in aqueous solution and are 10-times more potent than the prototype (unmodified) TGF-2 peptantagonist in inhibiting TGF-2 activity in vitro. One of these two new TGF-2 peptantagonists has been shown to potently prevent tissue injury, accelerate wound healing and reduce scarring in several animal injury models. These promising results have provided rationales for the proposed studies in the Phase II project. We hope the clinical availability of these two novel TGF-2 peptantagonists will be commercialized by large pharmaceutical companies, eventually directly benefiting individuals with various types of wounds including normal, impaired and chronic wounds. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop synthetic TGF-2 antagonists into wound healing agents for accelerating wound healing and reducing scarring. The clinical availability of these agents would benefit millions of patients who suffer from various types of wounds including normal, impaired and chronic wounds.