Protein Therapeutics Engineered to Regenerate Functional Heart Tissue

 心肌梗死（MI）是一个严重的公共卫生问题，每年影响150万美国人。 尽管治疗取得了进展，但MI后的一年生存率仅为37%。此外，由于心肌细胞死亡和随后的心脏瘢痕，存活的患者仍然遭受不可逆的心脏功能丧失。这些患者通常进展为充血性心力衰竭，这是一种日益增长的流行病，也是医疗保健系统的经济负担。银溪制药公司正在开发蛋白质疗法，以再生心肌梗死后的功能性心脏组织。我们使用计算和实验生物学的组合来设计基于生长因子的药物，称为智能生长因子（SGF），可以选择性地作用于受损的心肌细胞，以刺激它们的存活。我们有一个概念分子的证明，它可以显著地保留MI大鼠模型中的功能性心脏组织。该分子是生长因子和细胞靶向臂与支架蛋白的融合体。靶向臂和te支架对分子作用机制的明确贡献尚不清楚。在该计划的第一阶段，我们的目标是通过设计，构建和测试SGF变体来系统地探索每个分子组分对SGF功能的影响，从而更多地了解分子的设计如何有助于其功能。从这些测试中获得的理解将使设计更有效的疗法成为可能，这些疗法将在II期的扩展疗效研究中进行测试。

 DESCRIPTION (provided by applicant): Myocardial infarction (MI) is a serious public health problem affecting 1.5 million Americans each year. Despite advances in treatment, the one year survival rate following MI is only 37%. Furthermore, the patients who survive still suffer irreversible loss of heart function due to cardiomyocyte death and subsequent scarring of the heart. These patients often progress to congestive heart failure, which is a growing epidemic and economic burden on the health care system. Silver Creek Pharmaceuticals is developing protein therapeutics to regenerate functional heart tissue after myocardial infarction. We use a combination of computational and experimental biology to design growth factor based drugs called Smart Growth Factors (SGFs) that can act selectively on damaged cardiomyocytes to stimulate their survival. We have a proof of concept molecule that significantly preserves functional heart tissue in a rat model of MI. This molecule is a fusion of a growth factor and a cellular targeting arm to a scaffold protein. The explicit contributions of the targeting arm and te scaffold to the molecule's mechanism of action are unknown. In Phase I of this program we aim to learn more about how the design of the molecule contributes to its function by designing, building and testing SGF variants that systematically explore the effect of each molecule component on SGF function. The understanding gained from these tests will enable the design of even more effective therapies, which will be tested in expanded efficacy studies in Phase II.