Preclinical Development of a Novel Disease Modifying Therapy for Pulmonary Arterial Hypertension

项目摘要 Vasculonics是一家位于印第安纳州的小企业，正在开发一种新的治疗方法，以减少癌症的进展。 肺动脉高压（PAH）是一种具有高死亡率的衰弱性疾病。Vasculonics技术是 代谢不对称二甲基精氨酸的二甲基氨基水解酶（DDAH）的新调节剂 精氨酸（ADMA）和一个重要的分子机制，有助于肺以及心脏 PAH的病理学PAH患者和临床前模型中出现高水平的ADMA和降低的DDAH。在 除了减少一氧化氮的合成外，高水平的ADMA还诱导线粒体功能障碍，细胞死亡， 炎症和纤维化。持续的高ADMA水平可促进进行性血管重构 和PAH中观察到的心脏肥大。DDAH缺乏促进PAH的概念证明， 在转基因动物中DDAH的恢复改善了内皮功能， 并改变了肺和心脏的病理学，已经得到证实。目前，药物调节 DDAH途径不可用。Vasculonics正在开发一种新的DDAH小分子调节剂， 降低PAH中ADMA的病理水平和进行性血管病变。 Vasculonics已经将VN-317鉴定为一种新的先导系列，其在细胞内增强DDAH-1的转录， 基于DDAH启动子的筛选在PAH的临床前模型中，VN-317显示出稳健的疗效， 减少肺动脉阻塞，改善肺和心脏功能。Vasculonics 研究了这种化学支架的结构-活性关系（SAR），并证明了清晰的 DDAH调制的SAR。为了推进VN-317结构类别用于临床选择， 候选人，Vasculonics提出优化系列和额外的药物样特性 被设计为二苯乙烯模拟物的化学支架。结构不同的化合物将依次 在第1层和第2层试验中评价了理想的体外和体内药物能力特征。体内 将证实两种结构不同的电极导线在大鼠Sugen中减少PAH进展的有效性， 缺氧模型预期这些研究能够选择具有所需功能的候选分子。 药物的能力和有效性，推动两个先导分子的后期非临床CMC和安全性研究。 Vasculonics组建了一支经验丰富的科学和药物开发团队， 促进研究并将这种潜在的新疗法推广到PAH患者。拟议的研究将 帮助确保未来的赠款和投资者资金，以进一步发展。一个重要的市场存在， PAH治疗，估计价值超过40亿美元。因此，一种新的疾病 预期该疗法具有重大的医学和商业影响。

PROJECT SUMMARY Vasculonics, an Indiana-based small business is developing a novel therapy to reduce progression of pulmonary arterial hypertension (PAH), a debilitating disease with high mortality. Vasculonics technology is a novel modulator of dimethylarginine dimethylaminohydrolase (DDAH) which metabolizes asymmetric dimethyl arginine (ADMA) and an important molecular mechanism contributing to the pulmonary as well as cardiac pathology in PAH. High levels of ADMA and reduced DDAH occur in patients and preclinical models of PAH. In addition to reducing nitric oxide synthesis, high levels of ADMA induce mitochondrial dysfunction, cell death, inflammation and fibrosis. Persistent high ADMA levels can contribute to the progressive vascular remodeling and cardiac hypertrophy observed in PAH. The proof of concept that deficiency of DDAH promoted PAH and cardiovascular disease, and that restauration of DDAH in transgenic animals improved endothelial function, and modified the pathology in the lung and the heart, have been demonstrated. Currently, drugs modulating the DDAH pathway are not available. Vasculonics is developing a novel small molecule modulator of DDAH to reduce pathological levels of ADMA and the progressive vasculopathy in PAH. Vasculonics has identified VN-317 as a novel lead series which enhanced transcription of DDAH-1 in a DDAH promoter based screen. In a preclinical model of PAH, VN-317 has shown robust efficacy by reducing occlusion of lung arteries, and improving lung and cardiac functions. Vasculonics has investigated the structure-activity relationship (SAR) of this chemical scaffold and demonstrated clear SAR for DDAH modulation. In order to advance the VN-317 structural class for the selection of a clinical candidate, Vasculonics is proposing to optimize the drug-like properties of the series and additional chemical scaffold designed as stilbene-mimetics. Structurally distinct compounds will be sequentially evaluated for ideal in vitro and in vivo drug-ability characteristics in tier1 and tier2 assays. The in vivo efficacy of two structurally distinct leads will be confirmed for reducing PAH progression in a rat Sugen- hypoxia model. These studies are expected to enable selection of candidate molecules with desired drug-ability and efficacy to propel two lead molecules to late stage non-clinical CMC and safety studies. Vasculonics has assembled a highly experienced scientific and drug development team to pursue IND enabling studies and advance this potentially new therapy to PAH patients. The proposed studies will help secure future grants and investor funding for further development. A significant market exists for PAH therapy with an estimated value in excess of $4 billion. Therefore, a new disease modifying therapy is expected to have a major medical as well as commercial impact.