Renal Therapeutic Angiogenesis Using the Novel Biologic ELP-VEGF

使用新型生物 ELP-VEGF 进行肾脏治疗性血管生成

• 批准号: 10547049
• 负责人: Gene Leflore Bidwell
• 金额: $ 87.65万
• 依托单位: LEFLORE TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547049
• 关键词: 3-Dimensional; Adverse effects; Affect; Affinity; Aging; Angioplasty; Angiotensins; Animals; Architecture; Binding; Biological; Biological Assay; Biological Availability; Biomedical Engineering; Biopolymers; Breast Cancer Model; Canis familiaris; Cardiovascular system; Carrier Proteins; Cessation of life; Chemistry; Chimeric Proteins; Chronic; Chronic Kidney Failure; Clinical; Deterioration; Diabetes Mellitus; Dialysis procedure; Diet; Disease; Disease model; Dose; Drug Carriers; Dyslipidemias; Elastin; End stage renal failure; Endothelium; Engineering; Etiology; Funding; Future; General Population; Glomerular Filtration Rate; Goals; Growth; Growth Factor; Half-Life; Health Care Costs; Histologic; Hospitalization; Human; Hypertension; Injury to Kidney; Kidney; Kidney Diseases; Laboratories; Lead; Life Expectancy; Link; Maximum Tolerated Dose; Mediating; Microcirculation; Miniature Swine; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Nature; Patients; Pharmaceutical Preparations; Pharmacology Study; Phase; Plasma; Preclinical Testing; Predisposition; Prevalence; Process; Production; Proteins; Protocols documentation; Quality Control; Rattus; Recombinants; Recovery; Renal Artery Stenosis; Renal Blood Flow; Renal Vascular Disorder; Renal function; Research Contracts; Resolution; Risk; Rodent; Rodent Model; Safety; Serious Adverse Event; Severity of illness; Small Business Technology Transfer Research; Stents; Stroke; Technology; Testing; Therapeutic; Time; Tissues; Toxicity Tests; Toxicology; Treatment Efficacy; Treatment Protocols; Tubular formation; United States; VEGFA gene; Validation; Vascular Endothelial Growth Factors; Work; X-Ray Computed Tomography; Xenograft Model; angiogenesis; biomaterial compatibility; cardiovascular risk factor; clinically relevant; cohort; density; efficacy study; efficacy testing; good laboratory practice; hospitalization rates; immunogenicity; improved; in vivo; kidney vascular structure; mortality; novel; novel therapeutics; patient population; peptide drug; phase 1 study; phase 2 study; polypeptide; porcine model; pre-clinical; preclinical trial; renal artery; renal damage; residence; response; safety study; side effect; small molecule; therapeutic angiogenesis; therapeutic development; therapeutic protein; treatment arm; tumor growth

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.

抽象的。 慢性肾脏疾病（CKD）是一种进展性疾病，影响了几乎14％的普通人群，并且 在过去的20年中，这种疾病表现出友好的增长。 CKD患者的发生率较高 住院，更高的死亡率，较短的预期寿命以及其医疗保健费用高达5倍 比非CKD患者昂贵。那是缓慢，停止或扭转CKD的进展的治疗方法 重大的财务和临床影响。慢性肾血管疾病（RVD），通常与肾脏有关 动脉狭窄，可以确定肾功能并导致CKD和终末期肾脏疾病，最多可达15％ 患者。尽管可用于RVD的治疗方法，包括药物和经皮液压肾脏 在接受这些的一半以上的患者中，血管成形术，肾功能不会改善甚至有效 治疗。 Leflore Technologies开发了一种生物聚合物稳定的血管内皮生长形式 具有高肾脏结合的因子（VEGF）。 Leflore Technology的总体策略是使用生物聚合物-VEGF 热血管生成的融合以恢复肾脏微脉管系统并改善RVD和/或的肾功能 CKD。在此Sttr的I阶段部分中，非GLP效率和毒性测试与 生物聚合物融合的VEGF。使用肾动脉狭窄的猪模型 - 诱导RVD，血管成形术和支架 使用我们的生物聚合物稳定的VEGF的肾血管生成或没有治疗性肾血管生成。 审判。在治疗组中，肾功能和肾血管密度得到显着提高，组织学 相对于单独的血管成形术和支架支架，肾脏损伤的标记降低了。我们还进行了剂量 - 在大鼠中升级毒理学研究，这表明生物聚合物稳定的VEGF诱导了NO 剂量的明显副作用是计划治疗剂量的100倍。拟议的II期研究 将通过CGMP制造推进铅代理；化学，制造和控制测试；和 扩展的临床前GLP毒理学。计划的研究还将扩大我们先前的效力 通过在逐渐严重的肾脏疾病，随访较长的动物中测试，并使用 由糖尿病或高血压引起的多种CKD的啮齿动物模型以及我们的扩展研究 CKD的翻译猪模型将潜在的目标市场扩展到带支架治疗的RVD之外 整个慢性肾脏疾病。