A Therapeutic Agent for Radiation-induced Lung Fibrosis

描述(申请人提供)：肺纤维化是一组无法治愈的肺部疾病，死亡率高，其特征是炎症细胞浸润，成纤维细胞增殖，肺实质细胞外基质蛋白(ECM)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。在这些人中，每年有超过4万人死亡，相当于死于乳腺癌的人数，是死于囊性纤维症的人的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导致的结果，包括肺癌的放射治疗和化疗。放射性肺纤维化是癌症患者放射治疗的主要问题。在许多癌症中，治疗导致的纤维化往往限制了化疗和放射治疗的联合疗效。目前，肺纤维化尚无有效的非手术治疗方法。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-())在其发病机制中起重要作用。动物研究表明，用转化生长因子结合蛋白拮抗转化生长因子-1似乎可以改善肺纤维化。因此，合成的转化生长因子-β受体拮抗剂可能成为治疗肺纤维化的重要药物。我们最近开发了一类合成的转化生长因子β-肽拮抗剂(称为转化生长因子-β受体拮抗剂)，它能阻断转化生长因子-β受体，并拮抗培养细胞中转化生长因子-β的活性。在标准的动物皮肤损伤模型中，局部应用含有转化生长因子-(胃肽拮抗剂)的凝胶可促进伤口愈合并减轻纤维化。然而，在中性pH条件下，转化生长因子-β受体拮抗剂在水溶液中的溶解性较差，限制了其在肺纤维化治疗中的应用。在最近的研究中，我们开发了一种新型的聚乙二醇化的转化生长因子-β-肽拮抗剂(称为聚乙二醇化-转化生长因子-β-肽拮抗剂)，它在中性pH的水溶液中具有良好的溶解性，通过培养细胞测定了强大的拮抗活性，并通过环磷酰胺诱导的大鼠膀胱损伤测定了上皮再生活性。鼻腔给药这种聚乙二醇-转化生长因子-(肽拮抗剂)有效地预防博莱霉素诱导的小鼠肺纤维化，并减轻已建立的肺纤维化。这些结果表明，聚乙二醇-转化生长因子-β-1肽拮抗剂可能是一种有价值的防治人类肺纤维化的药物。我们假设我们的聚乙二醇-转化生长因子-(肽)拮抗剂在改善放射性肺纤维化方面是有效的。这项提议的主要目标是检验这一假设。拟议的第一阶段研究的结果应该为这种新型聚乙二醇式转化生长因子(胃肽拮抗剂)的第二阶段和临床试验提供基础。我们预测，我们的聚乙二醇-转化生长因子-(肽拮抗剂)的临床应用将使全球数百万患者受益。公共卫生相关性：这项提议的目标是开发新型的转化生长因子-β-肽拮抗剂，作为治疗放射性肺纤维化的候选药物，目前缺乏有效的治疗方法。这种药物的可获得性将使全球数百万患者受益。

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.