Renal Therapeutic Angiogenesis Using the Novel Biologic ELP-VEGF

抽象的。 慢性肾脏疾病(CKD)是一种进行性疾病，影响到近14%的普通人群， 在过去的20年里，这种疾病呈现出持续增长的趋势。慢性肾脏病患者有较高的 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，延缓、阻止或逆转慢性肾脏病进展的治疗方法本可以 对财务和临床都有重大影响。慢性肾血管疾病(RVD)，通常与肾脏 动脉狭窄，可恶化肾功能，并导致慢性肾脏病和终末期肾脏疾病，高达15% 病人。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，在接受血管成形术的患者中，超过一半的患者的肾功能没有改善甚至恶化。 治疗。LeFlore Technologies开发了一种生物聚合物稳定的血管内皮细胞生长形式 具有高肾脏结合力的因子(血管内皮生长因子)。乐福科技的整体战略是使用生物聚合物--血管内皮生长因子 融合术用于治疗性血管生成以恢复肾微血管和改善RVD和/或肾功能 CKD。在本试验的第一阶段期间，非GLP药效和毒性测试是用 生物聚合物融合的血管内皮生长因子。建立猪肾动脉狭窄致RVD、血管成形术和支架置入术的动物模型 使用我们的生物聚合物稳定的血管内皮生长因子在有或没有治疗性肾血管生成的情况下进行了临床前测试 审判。治疗组肾功能和肾血管密度明显改善，组织学观察 与血管成形术和支架植入术相比，肾脏损伤的标志物减少了。我们还做了一次剂量- 大鼠递增毒理学研究表明，生物聚合物稳定的血管内皮生长因子诱导NO 剂量高达计划治疗剂量的100倍时会有明显的副作用。建议的第二阶段研究 将通过cGMP制造、化学、制造和控制测试来推进先导剂；以及 扩展的临床前IND-启用GLP毒理学。计划中的研究还将延长我们先前的疗效 通过对患有逐渐严重的肾脏疾病的动物进行测试，并进行更长时间的随访，并使用 糖尿病或高血压引起的CKD的多只啮齿动物模型以及我们的扩展研究 CKD转化型猪模型将潜在目标市场扩展到支架治疗以外的RVD 慢性肾脏疾病作为一个整体。

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, 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. Leflore Technology’s overall strategy is to use the biopolymer-VEGF fusion for therapeutic angiogenesis to restore renal microvasculature and improve renal function in RVD and/or CKD. During the Phase I portion of this STTR, non-GLP efficacy and toxicity testing were conducted with the biopolymer-fused VEGF. Using a swine model of renal artery stenosis – induced RVD, angioplasty and stenting with or without therapeutic renal angiogenesis using our biopolymer-stabilized VEGF was tested in a preclinical trial. In the treatment arm, renal function and renal vascular density were significantly improved, and histological markers of renal injury were reduced, relative to angioplasty and stenting alone. We also performed a dose- escalating toxicology study in rats, which demonstrated that the biopolymer-stabilized VEGF induced no significant side-effects at doses up to 100 times the planned therapeutic dose. The proposed Phase II studies will advance the lead agent through cGMP manufacturing; chemistry, manufacturing and controls testing; and expanded preclinical IND-enabling GLP toxicology. The planned studies will also extend our prior efficacy studies by testing in animals with progressively more severe renal disease, with longer follow-ups, and using multiple rodent models of CKD caused by diabetes or hypertension as well as extended studies in our translational swine model of CKD to expand the potential target market beyond RVD treated with stenting to chronic kidney disease as a whole.