Nanocarrier-formulated anti-fibrotic peptides for cirrhosis - Fast Track SBIR

描述（由申请人提供）：本申请涉及肝纤维化药物的开发。肝硬化的10年死亡率为34- 66%，主要取决于肝硬化的原因;酒精性肝硬化的预后比原发性胆汁性肝硬化和肝炎肝硬化更差。这个应用程序将感兴趣的国家酒精滥用和酒精中毒研究所。肝硬化是由感染、酒精、过量脂肪、胆汁阻塞和铁或铜过载引起的瘢痕组织（纤维化）的积累而引起的长期肝损伤。大约40万美国人患有肝硬化。肝硬化影响着全球数百万患者，对临床医生来说仍然是一个尚未解决的挑战。鉴于与这种疾病相关的发病率/死亡率，迫切需要将新兴的抗纤维化分子转化为有效的疗法。加快已成功进行临床前研究的化合物的临床试验，有可能使急需的药物可用，并减少对肝脏移植的需求。肝硬化中的瘢痕形成过程由转化生长因子2（TGF 2）介导，其是最强大的纤维化剂。许多已知的TGF 2阻断剂主要是肽和蛋白质，一旦到达血流，由于快速降解和肾脏消除，这些肽和蛋白质不能容易地开发成药物。在本申请中，我们提出使用先进的基于亲和力的纳米载体技术来配制三种已知的TGF 2阻断剂肽。这将防止快速降解和消除，并将保持血液中活性抗纤维化肽的相对恒定浓度，从而促进这些肽药物从临床前到临床环境的转变。我们将合成适合于每种抗纤维化肽的纳米载体，并且我们将确定肽对这些纳米载体的亲和力（1/Kd，其中Kd是解离常数）。然后，我们将用适当的纳米载体配制这些肽，并评估大鼠体内的药代动力学。最后，我们将测试配制的肽在肝纤维化动物模型中的功效。 公共卫生相关性：肝硬化影响着全球数百万患者，对临床医生来说仍然是一个尚未解决的挑战。肝硬化是由转化生长因子2（TGF 2）介导的，并且许多已知的TGF 2作用的阻断剂是肽和蛋白质，由于它们一旦到达血流就迅速降解和肾脏消除，因此它们不能容易地开发成药物。在本申请中，我们提出使用先进的基于亲和性的纳米载体技术来配制已知的TGF 2肽阻断剂，该技术将防止它们的快速降解和消除，并将保持血液中抗纤维化肽的相对恒定的浓度。这将促进这些可能的肽药物从临床前到临床环境的过渡。

DESCRIPTION (provided by applicant): This application pertains to the development of Medication for Hepatic Fibrosis. Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis. This application will be of interest to National institute of Alcohol Abuse and Alcoholism. Cirrhosis is long-term liver damage from the buildup of scar tissue (fibrosis) caused by infections, alcohol, excess fat, bile obstruction, and iron or cupper overload. Approximately 400,000 Americans suffer from liver cirrhosis. Cirrhosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Given the morbidity/mortality associated with this disease, there is an urgent need for translation of emerging anti-fibrotic molecules into effective therapies. Expediting clinical trials for compounds that have successfully undergone preclinical studies has the potential to make much needed medications available and reduce the need for liver transplantations. The scarring process in liver cirrhosis is mediated by Transforming Growth Factor 2 (TGF2) which is the most powerful fibrotic agent. Many known blockers of TGF2 are mostly peptides and proteins which cannot be easily developed onto drugs due to rapid degradation and kidney elimination once it reaches the blood stream. In this application, we propose to formulate three known TGF2 blocker peptides using advanced affinity-based nanocarrier technology. This will prevent rapid degradation and elimination and will maintain relatively constant concentration of active anti-fibrotic peptides in the blood, thus facilitating the transition of these peptide drugs from pre-clinical to clinical setting. We will synthesize nanocarriers appropriate for each of the anti-fibrotic peptides and we will determine affinity (1/Kd, where Kd is the dissociation constant) of the peptide for these nanocarriers. We will then formulate these peptides with appropriate nanocarriers and evaluate the in vivo pharmacokinetics in rats. Finally we will test the efficacy of formulated peptides in animal models of liver fibrosis. PUBLIC HEALTH RELEVANCE: Cirrhosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Cirrhosis is mediated by Transforming Growth Factor 2 (TGF2) and many known blockers of TGF2 action are peptides and proteins which cannot be easily developed onto drugs due to their rapid degradation and kidney elimination once they reach the blood stream. In this application, we propose to formulate known peptide blockers of TGF2 using advanced affinity-based nanocarrier technology that will prevent their rapid degradation and elimination and will maintain relatively constant concentration of anti-fibrotic peptides in the blood. This will facilitate the transition of these possible peptide drugs from pre-clinical to clinical settings.