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，影响近14%的普通人群， 这种疾病在过去20年中呈无情增长趋势。CKD患者的发病率较高， 住院、死亡率更高、预期寿命更短，他们的医疗保健费用高达5倍 比非CKD患者更昂贵。因此，减缓、停止或逆转CKD进展的治疗可能具有以下作用： 一个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，可恶化肾功能，导致CKD和终末期肾病， 患者尽管RVD的治疗方法可用，包括药物和经皮腔内肾移植， 尽管有血管成形术，但在接受这些手术的患者中，超过一半的患者的肾功能没有改善甚至恶化。 治疗。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形式 高肾结合因子（VEGF）。莱弗洛雷科技公司的总体战略是利用生物聚合物--VEGF 用于治疗性血管生成的融合，以恢复RVD中的肾微血管并改善肾功能，和/或 CKD。在本STTR的I期部分，使用以下药物进行了非GLP疗效和毒性试验： 生物聚合物融合的VEGF。采用猪肾动脉狭窄模型诱导RVD，血管成形术和支架植入术 使用我们的生物聚合物稳定的VEGF进行治疗性肾血管生成或不进行治疗性肾血管生成， 审判在治疗组中，肾功能和肾血管密度显著改善， 相对于单独的血管成形术和支架植入术，肾损伤的标记物减少。我们还做了一个剂量- 在大鼠中进行的逐步增加的毒理学研究表明，生物聚合物稳定的VEGF不会诱导 在高达计划治疗剂量100倍的剂量下出现显著副作用。拟议的II期研究 将通过cGMP生产、化学、生产和控制测试推进先导药物;以及 扩展临床前IND使能GLP毒理学。计划中的研究还将扩展我们先前的疗效 通过在患有进行性更严重肾脏疾病的动物中进行测试，进行更长时间的随访，并使用 糖尿病或高血压引起的CKD的多种啮齿类动物模型以及我们的扩展研究 CKD的转化猪模型，以将潜在目标市场扩展到用支架治疗的RVD之外， 慢性肾脏疾病的整体。

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.