A Therapeutic Agent for Radiation-induced Lung Fibrosis

描述（由申请人提供）：肺纤维化是一组死亡率高的无法治愈的肺部疾病，其特征在于炎性细胞浸润、成纤维细胞增殖和细胞外基质蛋白（ECM）在肺实质中过度沉积。全球有500万人受到肺纤维化的影响。仅在美国，就有20万人患有这种疾病。其中每年有4万多人死亡，相当于死于乳腺癌的人数，是死于囊性纤维化的人数的40倍。肺纤维化对生活质量的影响是严重的。不明原因的肺纤维化称为特发性肺纤维化（IPF）。肺纤维化也是多种原因的结果，包括肺肿瘤的放疗和化疗。放射诱导的肺纤维化是癌症患者放射治疗的主要关注点。治疗诱导的纤维化通常限制了化疗和放疗组合在许多癌症中的疗效。目前，对于肺纤维化没有有效的非手术治疗。因此，迫切需要开发预防和改善肺纤维化的治疗剂。越来越多的证据表明，转化生长因子（TGF-β）在其发病机制中起重要作用。动物研究表明，通过用TGF-β结合蛋白治疗来拮抗TGF-β似乎可以改善肺纤维化。因此，合成的TGF-β拮抗剂可作为肺纤维化的重要治疗剂。我们最近开发了一类合成的TGF-β肽拮抗剂（称为TGF-β肽拮抗剂），其阻断TGF-β与TGF-β受体的结合并拮抗培养细胞中的TGF-β活性。在标准动物皮肤损伤模型中局部应用含有TGF-β肽拮抗剂的凝胶促进伤口愈合并减弱纤维化。然而，TGF-β的使用在最近的研究中，我们开发了一种新的聚乙二醇化TGF-β肽拮抗剂（称为PEG-TGF-β肽拮抗剂），其在中性pH的水溶液中具有优异的溶解性，使用培养的细胞测量的有效拮抗剂活性，和上皮再生活性，如在大鼠中使用环磷酰胺诱导的膀胱损伤所测定的。鼻内给予这种PEG-TGF-β肽拮抗剂有效地预防了博莱霉素诱导的小鼠肺纤维化，并减弱了已建立的肺纤维化。这些结果表明PEG-TGF-β肽拮抗剂可能是预防和治疗人类肺纤维化的有价值的治疗剂。我们假设我们的PEG-TGF-β肽拮抗剂在改善辐射诱导的肺纤维化中是有效的。本提案的主要目的是检验这一假设。I期研究的结果将为这种新型PEG-TGF-β肽拮抗剂的II期和临床试验提供基础。我们预测，我们的PEG-TGF-β肽拮抗剂的临床可用性将使全球数百万患者受益。公共卫生相关性：该提案的目标是开发新型TGF-β肽拮抗剂作为治疗目前缺乏有效治疗的放射诱导的肺纤维化的候选药物。这种药物的供应将使全世界数百万患者受益。

DESCRIPTION (provided by applicant): Lung fibrosis, a group of incurable lung diseases with high mortality rates, is characterized by inflammatory cell infiltration, fibroblast proliferation, and excessive deposition of extracellular matrix proteins (ECM) in lung parenchyma. Globally, five million people are affected by lung fibrosis. In the U.S. alone, 200,000 suffer from this disease. Of these more than 40,000 die annually, equivalent to the number who die from breast cancer, and forty times more than those who die from cystic fibrosis. The effect of lung fibrosis on quality of life is severe. Lung fibrosis of unknown causes is known as idiopathic pulmonary fibrosis (IPF). Lung fibrosis also develops as a consequence of multiple causes, including radiotherapy and chemotherapy for lung neoplasms. Radiation-induced lung fibrosis is a major concern for radiotherapy for cancer patients. Therapy-induced fibrosis often limits the efficacy of the combination of chemotherapy and radiotherapy in numerous cancers. Currently, there are no effective non-surgical treatments for lung fibrosis. Hence there is an urgent need to develop therapeutic agents that prevent and ameliorate lung fibrosis. Accumulating evidence indicates that transforming growth factor-( (TGF-() plays an important role in its pathogenesis. Animal studies have shown that antagonizing TGF-( by treatment with TGF-( binding proteins appears to ameliorate lung fibrosis. Therefore synthetic TGF-( antagonists may serve as important therapeutic agents for lung fibrosis. We recently developed a class of synthetic TGF-( peptide antagonists (termed TGF-( peptantagonists) that block TGF-( binding to TGF-( receptors and antagonize TGF-( activity in cultured cells. Topical application of gel containing a TGF-( peptantagonist in standard animal skin injury models promotes wound healing and attenuates fibrosis. However, the use of TGF-( peptantagonists to treat lung fibrosis is limited by its poor solubility in aqueous solution at neutral pH. In recent studies, we have developed a novel pegylated TGF-( peptantagonist (termed PEG-TGF-( peptantagonist) which has excellent solubility in aqueous solution at neutral pH, potent antagonist activity as measured using cultured cells, and epithelial regeneration activity as determined using cyclophosphamide-induced bladder injury in rats. Intranasal administration of this PEG-TGF-( peptantagonist effectively prevents bleomycin-induced lung fibrosis in mice and attenuates established lung fibrosis as well. These results suggest that PEG-TGF-( peptantagonist may be a valuable therapeutic agent for prevention and treatment of lung fibrosis in humans. We hypothesize that our PEG-TGF-( peptantagonist is effective in ameliorating radiation-induced lung fibrosis. The major goal of this proposal is to test this hypothesis. The results from the proposed phase I studies should provide the basis for Phase II and clinical trials of this novel PEG-TGF-( peptantagonist. We predict that the clinical availability of our PEG-TGF-( peptantagonist will benefit millions of patients worldwide. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop novel TGF-( peptantagonist as a drug candidate for treating radiation-induced lung fibrosis which currently lacks effective treatments. The availability of such drug will benefit millions of patients worldwide.