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，影响近14%的普通人群， 在过去的二十年里，这种疾病的发病率呈持续增长的趋势。CKD患者的发病率较高， 住院率，死亡率更高，预期寿命更短，他们的医疗保健费用高达5倍以上 比非CKD患者更昂贵。因此，减缓、停止或逆转CKD进展的治疗可以 具有重大的经济和临床影响。慢性肾血管疾病（RVD），通常与 肾动脉狭窄，可使肾功能恶化，并导致高达15%的CKD和终末期肾病 病人。尽管RVD的治疗方法可用，包括药物和经皮腔内肾移植， 在血管成形术（PTRA）中，超过一半的患者的肾功能没有改善甚至恶化 接受这些治疗。莱弗洛雷科技公司开发了一种生物聚合物稳定的血管 内皮生长因子（VEGF）与肾结合率高。本第一阶段短期测试报告将测试PTRA的可行性 在一项临床前试验中， 慢性RVD的猪模型。最近，我们已经证明，我们的生物聚合物融合大大稳定 生长因子从降解和血浆或组织清除，并介导肾脏中的沉积 肾内给药后。此外，我们有令人信服的初步证据表明我们的生物聚合物- 递送的VEGF对于恢复猪模型中的肾功能是高度有效的。拟定的I期 研究将进行临床前的有效性和安全性试验PTRA和支架结合我们的 生物聚合物递送的VEGF与单独PTRA和支架植入术或PTRA和支架植入术联合标准治疗相比 药物治疗.这些研究将检查这种策略相对于当前临床标准的有效性 治疗的有效性，该策略在早期，中期和晚期RVD的有效性，以及长期有效性和 干预的安全性。未来的II期研究将涉及良好生产和规范（GMP） 生产我们的重组生物制剂;化学，制造和控制测试;并扩大 临床前IND使能毒理学。

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.