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

基本信息

批准号：
10705193
负责人：
Gene Leflore Bidwell
金额：
$ 96.08万
依托单位：
LEFLORE TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
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/10705193
关键词：
3-Dimensional Adverse effects Affect Affinity Aging Angioplasty Angiotensins Animals Architecture Binding Biological Biological Assay Biological Availability Biomedical Engineering Biopolymers Blood Vessels 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 Good Manufacturing Process Growth Growth Factor Half-Life Health Care Costs Histologic Hospitalization Human Hypertension Injury to Kidney Kidney Kidney Diseases Laboratories Lead Life Expectancy Link Marketing 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 manufacture 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

项目摘要

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）是一种计划疾病，几乎占普通人群的14％，并且在过去的20年中，Thisase表现出无情的增长。住院，更大的art虫，较短的预期寿命以及其医疗保健费用高达5倍因此，比CKD患者昂贵。慢性肾血管疾病（RVD）动脉狭窄，可能会恶化肾功能，并导致CKD和肾脏疾病多达15％尽管有RVD药物和肌肉肾肾肾肾肾肾肾脏肾肾脏肾脏肾脏的可用性血管成形术，肾功能不会改善甚至恶化。 Leflore Technologies开发具有高肾脏结合的因素（VEGF）。用于治疗性血管生成的融合，以恢复肾脏肾脏微血管箱并改善RVD中的肾功能 CKD。生物聚合物融合的VEGF。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。在治疗组中，肾功能和肾脏血管密度显着提高，组织学相对于单独的血管成形术，肾脏损伤的标记减少了。在大鼠中升级毒理学研究，该研究证明了生物聚合物稳定的VEGF诱导NO 大量副作用的剂量高达计划的治疗剂量的100倍。将通过CGMP制造，制造和控制测试来推动铅代理。扩展的临床前GLP毒理学也将延长我们先前的效率通过对患有更严重肾脏疾病的动物进行测试，随访时间更长，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使用RVD以外的RVD，整个慢性肾脏疾病。