IgA Protease Therapy of IgA Nephropathy in Animal Models

IgA 蛋白酶治疗 IgA 肾病动物模型

• 批准号: 7142122
• 负责人: Andrew George Plaut
• 金额: $ 29.59万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142122
• 关键词: Haemophilus influenzae; IgA nephropathy; Streptococcus; bacterial proteins; biotherapeutic agent; disease /disorder model; drug screening /evaluation; endopeptidases; immunoglobulin A; immunopathology therapy; laboratory mouse; nonhuman therapy evaluation; pharmacokinetics; recombinant proteins

DESCRIPTION (provided by applicant): IgA nephropathy is a common, chronic kidney disease characterized by the deposition of lgA1-predominant immune complexes in the renal glomerulus. These complexes, whose antigens are unknown, appear early in life, and they eventually lead to glomerular injury, loss of renal function, and the need for dialysis or transplantation. Because loss of function takes decades to develop, there is an opportunity to intervene before the onset of renal insufficiency. We propose to develop a mouse model of IgA nephropathy to determine if lgA1 can be removed by injections of bacterial IgA proteases. These enzymes are endopeptidases produced by bacteria (Streptococcus, Neisseria, Haemophilus, and Clostridium species), and irrespective of their bacterial origin or catalytic mechanism, they share high substrate specificity for human lgA1 proteins. To produce the model of lgA1 deposition disease, mice will be injected with immune complexes of human lgA1, which immunofluorescence shows are deposited in the renal glomerular mesangium. Preliminary studies indicate that injections of recombinant H. influenzae IgA protease markedly reduce the glomerular burden of lgA1 in the mouse kidney. We will extend these studies to test for renal dysfunction in the mouse model, determine if IgA proteases can reverse these abnormalities, and to quantitate the effects of the protease in experiments appropriately powered for statistical analysis. We will also test a metal-dependent IgA protease from Streptococcus sanguis, an enzyme with unique attributes perhaps useful for treatment of the human illness. Finally, we will establish the elimination half-life and apparent volume of distribution of the IgA proteases in treated mice. This model of IgA nephropathy is based on human lgA1, essential for our long-term goal of removing IgA from the kidney of patients with the disease.

描述（由申请人提供）：IgA 肾病是一种常见的慢性肾脏疾病，其特征是肾小球中以 lgA1 为主的免疫复合物沉积。这些抗原未知的复合物在生命早期出现，最终导致肾小球损伤、肾功能丧失以及需要透析或移植。由于功能丧失需要几十年的时间才能形成，因此有机会在肾功能不全发生之前进行干预。我们建议开发 IgA 肾病小鼠模型，以确定是否可以通过注射细菌 IgA 蛋白酶来去除 lgA1。这些酶是由细菌（链球菌、奈瑟菌、嗜血杆菌和梭状芽胞杆菌）产生的肽链内切酶，无论其细菌来源或催化机制如何，它们都对人类 lgA1 蛋白具有高度底物特异性。为了制作IgA1沉积病模型，将向小鼠注射人IgA1的免疫复合物，免疫荧光显示该复合物沉积在肾小球系膜中。初步研究表明，注射重组流感嗜血杆菌 IgA 蛋白酶可显着降低小鼠肾脏中 lgA1 的肾小球负担。我们将扩展这些研究，以测试小鼠模型中的肾功能障碍，确定 IgA 蛋白酶是否可以逆转这些异常，并在适当支持统计分析的实验中量化蛋白酶的影响。我们还将测试来自血链球菌的金属依赖性 IgA 蛋白酶，这种酶具有独特的属性，可能对治疗人类疾病有用。最后，我们将确定治疗小鼠中 IgA 蛋白酶的消除半衰期和表观分布体积。这种 IgA 肾病模型基于人类 lgA1，这对于我们从疾病患者肾脏中去除 IgA 的长期目标至关重要。