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MMP-targeted viral gene delivery vectors for treatment of infarcted heart

用于治疗梗塞心脏的 MMP 靶向病毒基因递送载体

基本信息

批准号：
8969204
负责人：
Junghae Suh
金额：
$ 24.02万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969204
关键词：
Adenoviruses Adverse effects Affect Anterior Arteries Atherosclerosis Behavior Binding Capsid Cardiac Cardiovascular Diseases Cell Surface Receptors Cells Congestive Heart Failure Contrast Media Data Dependovirus Detection Development Device or Instrument Development Devices Digestion Disease Dose Engineering Exhibits Exposure to Functional disorder Gelatinase A Gelatinase B Gene Delivery Gene Expression Generations Genes Goals Heart Heart Diseases High temperature of physical object Image Imaging Device Immune response In Vitro Knowledge Lead Left Ligation Liver Matrix Metalloproteinases Modeling Molecular Models Mus Mutagenesis Myocardial Infarction Organ PET/CT scan Pathogenesis Patient Care Peptide Hydrolases Performance Positioning Attribute Property RNA Interference Research Personnel Route Sensitivity and Specificity Serotyping Site Skeletal Muscle Solid Specificity Testing Therapeutic Tissues Transcriptional Regulation Transgenes Trypsin Variant Viral Vector Virus adeno-associated viral vector base cellular transduction design extracellular gene therapy heart cell in vivo in vivo Model in vivo imaging innovation molecular imaging molecular modeling overexpression pre-clinical programs promoter public health relevance receptor receptor binding skills targeted delivery therapeutic gene transduction efficiency vector viral gene delivery

项目摘要

DESCRIPTION: Adeno-associated viruses (AAV) have demonstrated great promise for gene therapy of a variety of heart diseases. Several AAV variants, such as AAV serotype 9 (AAV9), have been identified with high delivery efficiencies in cardiac cells. Unfortunately, the vectors still suffer from significant delivery to non-target sites, such as liver and skeletal muscles. Consequently, AAV vectors may need to be delivered via invasive administration routes to physically localize gene delivery to the heart. Most current strategies to achieve targeted delivery focus on enabling vectors to bind cell surface receptors that are overexpressed on target diseased cells. Unfortunately, identification of single receptors that lead to high delivery specificity has been difficult to achieve. As an alternate strategy, we hypothesize AAV vectors can be designed to target extracellular proteases - a hallmark of several cardiovascular diseases, including myocardial infarction. The protease-activated viruses (PAVs) will be unable to transduce cardiac cells until they detect pathological concentrations of specific extracellular proteases. To enhance the gene delivery specificity, we will combine transcriptional control with protease activation. In particular, the PAVs will carry a transgene driven by a heart- specific promoter. If only transcriptional control is used, the gene expression will occur in all heart tissues. If only protease-activation is used, then gene expression may occur in off-target sites also exhibiting elevated protease levels. By combining transcriptional control with protease-activation, we aim to limit gene expression to heart tissues that are also diseased. We have promising proof-of-concept data both in vitro and in vivo showing we have successfully created the first generation of PAVs. At low levels of proteases, the vectors are unable to bind their cell surface receptor and display negligible cellular transduction. Upon exposure to extracellular proteases, either a single target protease or a combination of two different proteases, the PAVs "switch on" their cell receptor binding behavior and dramatically increase their transduction efficiency. In aim 1, we will generate a toolkit of single- or dual-input AAV9-based PAVs that are responsive to extracellular proteases known to be elevated in myocardial infarction. In aim 2, we will conduct molecular imaging with protease-activatable contrast agents to detect protease activity in the infarcted heart. The imaging studies will help guide and validate the design and performance of protease-targeted AAV9 vectors. If successful, the studies proposed here will lay the preclinical groundwork for the development of vectors that can deliver genetic therapies specifically to diseased heart tissues.