A Preclinical Trial of Therapeutic Angiogenesis Plus Angioplasty and Stenting for Renal Vascular Disease

治疗性血管生成加血管成形术和支架置入术治疗肾血管疾病的临床前试验

基本信息

批准号：
9249339
负责人：
Gene Leflore Bidwell
金额：
$ 21.64万
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 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249339
关键词：
3-Dimensional Adverse effects Affect Affinity Angioplasty Angiotensins Architecture Binding Biological Availability Biological Products Biomedical Engineering Biopolymers Carrier Proteins Cessation of life Chemistry Chimeric Proteins Chronic Chronic Kidney Failure Clinical Collection Deposition Deterioration Dialysis procedure Disease Dose Drug Carriers Elastin End stage renal failure Engineering Family suidae Fibrosis Future General Population Glomerular Filtration Rate Goals Gold Growth Growth Factor Half-Life Health Care Costs Hospitalization Human In Vitro Infusion procedures Injury Intervention Kidney Kidney Diseases Lead Licensing Life Expectancy Link Mediating Microcirculation Modeling Morbidity - disease rate Mus Myocardial Infarction NOEL Nature Patients Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Plasma Predisposition Prevalence Production Proteins Recombinants Recovery Renal Artery Stenosis Renal Blood Flow Renal Cell Carcinoma Renal Vascular Disorder Renal function Resolution Risk Safety Schedule Signal Transduction Small Business Technology Transfer Research Stents Stroke Technology Testing Therapeutic Time Tissues Toxic effect Toxicology Treatment Efficacy Tubular formation United States VEGFA gene Vascular Endothelial Growth Factors X-Ray Computed Tomography angiogenesis biomaterial compatibility cardiovascular risk factor commercialization density efficacy testing hemodynamics human disease immunogenicity improved in vivo kidney vascular structure mortality novel novel therapeutic intervention novel therapeutics patient population peptide drug phase 1 study phase 2 study polypeptide pre-clinical preclinical efficacy preclinical evaluation preclinical safety preclinical trial residence response small molecule standard of care therapeutic angiogenesis therapeutic development 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 (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.

抽象的。慢性肾病 (CKD) 是一种进行性疾病，影响了近 14% 的普通人群，这种疾病在过去20年中呈持续增长趋势。 CKD 患者的发病率较高住院率更高、死亡率更高、预期寿命更短，而且医疗费用高达 5 倍比非 CKD 患者昂贵。因此，减缓、停止或逆转 CKD 进展的治疗可以具有重大的财务和临床影响。慢性肾血管疾病（RVD），通常与肾动脉狭窄，可使肾功能恶化，导致高达 15% 的 CKD 和终末期肾病的患者。尽管 RVD 的治疗方法包括药物和经皮腔内肾穿刺血管成形术（PTRA），超过一半患者的肾功能没有改善甚至恶化正在接受这些治疗。 Leflore Technologies 开发了一种生物聚合物稳定形式的血管内皮生长因子 (VEGF) 具有高肾结合力。第一阶段 STTR 将测试 PTRA 的可行性以及在临床前试验中使用我们的生物聚合物稳定的 VEGF 进行支架置入术以及治疗性肾血管生成慢性 RVD 猪模型。最近，我们证明了我们的生物聚合物融合极大地稳定了来自降解和血浆或组织清除的生长因子并介导在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 对于恢复猪模型的肾功能非常有效。拟议的第一阶段研究将结合我们的研究开展 PTRA 和支架置入术的临床前疗效和安全性试验生物聚合物递送的 VEGF 与单独 PTRA 和支架置入术或 PTRA 和支架置入术与标准护理相比药物治疗。这些研究将检验该策略相对于当前临床标准的有效性护理、该策略在早期、中期和晚期 RVD 的疗效以及长期疗效和干预的安全性。未来的第二阶段研究将涉及良好生产和实践（GMP）生产我们的重组生物制剂；化学、制造和控制测试；并扩大了临床前 IND 毒理学。