A Preclinical Trial of Therapeutic Angiogenesis Plus Angioplasty and Stenting for Renal Vascular Disease

抽象的。 慢性肾脏疾病(CKD)是一种进行性疾病，几乎占总人口的14%， 在过去的20年里，这种疾病呈现出持续增长的趋势。慢性肾脏病患者的发病率较高 住院、更高的死亡率、更短的预期寿命，以及他们的医疗费用高达5倍 费用比非CKD患者高。因此，减缓、阻止或逆转慢性肾脏病进展的治疗方法可能 有重大的财务和临床影响。慢性肾血管疾病(RVD)，通常与 肾动脉狭窄，可恶化肾功能，并导致CKD和终末期肾脏疾病，高达15% 病人的数量。尽管有治疗RVD的方法，包括药物和经皮腔内肾脏 血管成形术(PTRA)，超过一半的患者肾功能没有改善甚至恶化 正在接受这些治疗。LeFlore Technologies开发了一种生物聚合物稳定形式的血管 具有高肾脏结合力的内皮生长因子(VEGF)。这个第一阶段的测试将测试PTRA的可行性 在临床前试验中，使用我们的生物聚合物稳定的血管内皮生长因子进行支架置入和治疗性肾血管生成 慢性RVD的猪模型。最近，我们证明了我们的生物聚合物融合极大地稳定了 来自降解和血浆或组织清除的生长因子，并介导肾脏中的沉积 在肾内给药之后。此外，我们有令人信服的初步证据表明我们的生物聚合物- 血管内皮细胞生长因子对恢复猪肾功能有很好的效果。建议的第一阶段 研究将进行PTRA和支架植入术的临床前疗效和安全性试验 生物聚合物输送的血管内皮生长因子与单纯PTRA和支架植入术或PTRA和标准护理支架植入术的比较 药物疗法。这些研究将相对于目前的临床标准来检验这一策略的有效性。 该策略在早期、中期和晚期RVD的疗效，以及长期疗效和 干预的安全性。未来的第二阶段研究将涉及良好的制造和实施(GMP) 我们的重组生物制剂的生产；化学、制造和控制测试；并扩大 临床前支持IND的毒理学。

Abstract. Chronic kidney disease (CKD) is a progressive disorder affecting almost 14% of the general population, and this disease has shown a relentless growth over the past 2 decades. Patients with CKD have higher rates of hospitalization, greater mortality, shorter life expectancy, and their healthcare costs are up to 5 times more expensive than non-CKD patients. Thus, treatments to slow, halt, or reverse the progression of CKD could have a significant financial and clinical impact. Chronic renal vascular disease (RVD), often associated with renal artery stenosis, can deteriorate renal function and lead to CKD and end-stage renal disease in up to 15% of patients. Despite the availability of treatments for RVD including drugs and percutaneous transluminal renal angioplasty (PTRA), renal function does not improve or even deteriorates in over half of the patients undergoing these treatments. Leflore Technologies has developed a biopolymer-stabilized form of vascular endothelial growth factor (VEGF) with high renal binding. This Phase I STTR will test the feasibility of PTRA and stenting plus therapeutic renal angiogenesis with our biopolymer-stabilized VEGF in a preclinical trial using a swine model of chronic RVD. Recently, we have demonstrated that our biopolymer fusion greatly stabilizes the growth factor from degradation and plasma or tissue clearance and mediates deposition in the kidney following intrarenal administration. Furthermore, we have compelling preliminary evidence that our biopolymer- delivered VEGF is highly efficacious for restoring renal function in the swine model. The proposed Phase I studies will carry out preclinical efficacy and safety trials of PTRA and stenting in combination with our biopolymer-delivered VEGF compared to PTRA and stenting alone or PTRA and stenting with standard of care pharmacotherapy. These studies will examine the efficacy of this strategy relative to current clinical standard of care, the efficacy of this strategy at early-, middle-, and late-stage RVD, and the long-term efficacy and safety of the intervention. Future Phase II studies will involve good manufacturing and practice (GMP) production of our recombinant biological agent; chemistry, manufacturing and controls testing; and expanded preclinical IND-enabling toxicology.