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

描述(申请人提供)：本申请涉及治疗肝纤维化药物的开发。已确诊的肝硬变的10年死亡率为34-66%，主要取决于肝硬变的病因；酒精性肝硬变的预后比原发性胆汁性肝硬变和肝炎所致的肝硬变更差。这项申请将对国家酒精滥用和酒精中毒研究所感兴趣。肝硬变是由于感染、酒精、过量脂肪、胆汁阻塞以及铁或铜过量而导致的疤痕组织(纤维化)积聚造成的长期肝脏损害。大约有40万美国人患有肝硬变。肝硬变影响全球数百万患者，对临床医生来说仍然是一个悬而未决的挑战。鉴于这种疾病的发病率/死亡率，迫切需要将新出现的抗纤维化分子转化为有效的治疗方法。加快对已成功进行临床前研究的化合物的临床试验，有可能提供急需的药物，并减少对肝脏移植的需求。肝硬变的瘢痕形成过程是由转化生长因子2(TGF2)介导的，TGF2是最强的纤维化因子。许多已知的TGF2阻滞剂大多是多肽和蛋白质，一旦到达血流，由于迅速降解和肾脏消除，不易开发成药物。在这项应用中，我们建议使用先进的基于亲和力的纳米载体技术来制备三种已知的TGF2阻滞剂多肽。这将防止快速降解和消除，并将在血液中保持相对恒定的活性抗纤维化多肽浓度，从而促进这些多肽药物从临床前过渡到临床。我们将合成适合每个抗纤维化多肽的纳米载体，并确定这些纳米载体的多肽的亲和力(1/Kd，其中Kd是解离常数)。然后，我们将用合适的纳米载体来配制这些多肽，并评估它们在大鼠体内的药代动力学。最后，我们将测试配制的多肽在肝纤维化动物模型中的疗效。 公共卫生相关性：肝硬变影响全球数百万患者，对临床医生来说仍然是一个悬而未决的挑战。肝硬变是由转化生长因子2(TGF2)介导的，许多已知的TGF2作用阻滞剂是多肽和蛋白质，一旦到达血流，它们就不容易被开发成药物，因为它们被迅速降解和肾脏消除。在这项应用中，我们建议使用先进的基于亲和力的纳米载体技术来研制已知的TGF2多肽阻滞剂，这种技术将防止它们的快速降解和消除，并将保持抗纤维化多肽在血液中的相对恒定浓度。这将促进这些可能的多肽药物从临床前向临床环境的过渡。

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.