Genome engineering therapeutics for cystinuria and its metabolic consequences.

胱氨酸尿症的基因组工程疗法及其代谢后果。

基本信息

批准号：
10588590
负责人：
MATTHEW H WILSON
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588590
关键词：
Acute Adult Affect Amino Acids Animal Model Animals Blood Cells Chronic Chronic Kidney Failure Clinical Cystine Cystinuria Data Dependovirus Development Disease Disease model Experimental Designs Feasibility Studies Foundations Gene Delivery Gene Mutation Gene Transfer Genetic Genetic Recombination Genome engineering Glutathione Grant Health Human Hybrids Image Inherited Injury Injury to Kidney Kidney Kidney Calculi Kidney Diseases Knowledge Mediating Medical Metabolic Metabolic Pathway Mission Modeling Modification Morbidity - disease rate Mus Mutation Neonatal Organ Organoids Phenotype Plague Plasma Proximal Kidney Tubules Recombinants Research Site Sodium Chloride Technology Technology Transfer Testing Therapeutic Tissues Trans-Splicing Transgenes Urine Validation Veterans Water absorption adeno-associated viral vector cellular transduction in vivo innovation mass spectrometric imaging military veteran molecular targeted therapies mortality mouse model neutralizing antibody novel novel therapeutics pre-clinical preclinical study prevent reconstitution side effect transgene delivery transgene expression translational therapeutics urinary vector

项目摘要

ABSTRACT Cystinuria is an inherited human kidney disease with significant morbidity affecting 1 in 7000, including veterans. The disease is caused by mutation of genes involved in renal cystine transport resulting in elevated urinary cystine with kidney stone formation. With the genetic basis of the disorder defined (mutation in SLC3A1, cystinuria type A), opportunities for targeted molecular therapies exist. Building upon our previous grant, we propose an innovative experimental design to demonstrate long-term phenotypic correction of cystinuria in an intact animal using a combination of transposon and adeno-associated virus (AAV) technologies. In specific aim 1, we will test the ability of hybrid AAV-piggyBac transposon technology to mediate long-term transgene expression in mouse kidney and correct cystinuria in a Slc3a1-/- mouse model. In specific aim 2, we will test the ability of novel proximal tubule targeted AAV to deliver transgenes to proximal tubule cells in mice in vivo. In both aims, we will test delivery to and evaluate for long-term transgene expression in both neonatal and adult mice. In specific aim 3, we propose to bridge our foundational pre-clinical studies to human application by testing AAV delivery to human kidney organoids including cystinuria organoids. Our innovative but feasible studies will expand use of AAV and transposon technology for kidney gene delivery and lay a pre-clinical foundation for ultimate human therapeutic application for kidney disease in veterans and others.

抽象的 Cystinuria是一种遗传性的人类肾脏疾病，其发病率显着影响7000人，包括退伍军人。该疾病是由参与肾胱氨酸转运的基因突变引起的，导致尿升高与肾结石形成的胱氨酸。与定义的疾病的遗传基础（SLC3A1中的突变， A）囊肿症，存在靶向分子疗法的机会。在我们以前的赠款的基础上，我们提出了一种创新的实验设计，以证明对囊肿的长期表型校正完整的动物结合了转座子和腺相关病毒（AAV）技术。在特定的目标1中，我们将测试混合AAV-piggybac Transposon技术长期介导的能力小鼠肾脏中的转基因表达，并在SLC3A1 - / - 小鼠模型中校正囊肿。在特定的目标2中，我们将测试针对AAV的新型近端小管的能力体内。在这两个目标中，我们都将测试并评估新生儿和成年小鼠。在特定目标3中，我们建议通过测试AAV递送到包括囊肿器官在内的人类肾脏器官。我们的创新但可行研究将扩大对肾脏基因递送的AAV和Transposon技术的使用，并进行临床前进行在退伍军人和其他人中为肾脏疾病的最终人类治疗基金会。