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Developing a Temporally-Regulated Gene Therapy for Therapeutic Angiogenesis

开发用于治疗性血管生成的时间调控基因疗法

基本信息

批准号：
10535141
负责人：
Mai Ngo
金额：
$ 6.72万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535141
关键词：
Affect Alternative Therapies Angiogenic Factor Angioplasty Arteries Behavior Biocompatible Materials Biological Blood Vessels Blood flow Boston Bypass Cardiovascular Diseases Cause of Death Cell Therapy Cells Cessation of life Chronic Clinic Clinical Trials Complex Development Dose Endothelial Cells Engineering Event Gene Delivery Gene Expression Gene Expression Regulation Generations Genes Genetic Grant Growth Growth Factor Growth Factor Gene Half-Life Health Hindlimb Hypoxia Hypoxia Inducible Factor Immunotherapy Impairment In Vitro Ischemia Maturation-Promoting Factor Measures Mentors Modeling Molecular Operative Surgical Procedures Oxygen Patients Perfusion Persons Play Process Proliferating Quality of life Recombinant Proteins Recovery Regenerative Medicine Response Elements Role Signal Transduction Site Stroke Switch Genes Testing Tissue Engineering Tissues Training Transcriptional Regulation Translating Tube Universities Vascular blood supply Vascularization Writing angiogenesis career cellular engineering collaborative environment comorbidity cost design disability experience gene therapy genetic element genetically modified cells improved in vitro Model in vivo in vivo Model insight interest ischemic cardiomyopathy next generation novel paracrine patient population recruit sensor stem cells success symposium synthetic biology therapeutic angiogenesis tool

项目摘要

Project Summary/Abstract Cardiovascular diseases affect millions of patients worldwide and account for nearly a third of deaths globally. Ischemia, or a reduced blood supply, occurs in many cardiovascular diseases and is a pressing health challenge. While current treatments primarily focus on re-vascularization of existing blood vessels, a significant sub- population of patients are unable to tolerate the associated surgical procedures due to existing comorbidities. Thus, there is great interest in developing strategies for therapeutic angiogenesis, which seeks to stimulate new vascularization at the ischemic site. While many gene and cell therapies for therapeutic angiogenesis have been tested in clinical trials, a clear benefit for patients remains to be seen. To date, most gene therapies deliver one or two genes to the ischemic site, while cell therapies deliver progenitor or stem cells to produce paracrine factors and self-organize into vasculature. A central limitation of these therapies is the inability to control the temporal presentation of the expressed genes or secreted factors. Angiogenesis is a complex and temporally regulated process, in which angiogenic factors first initiate the formation of a primitive vascular network before maturation factors promote mural cell recruit and vessel stabilization. While studies with growth factors suggest that sequential delivery of angiogenic and maturation factors is beneficial for establishing functional vasculature, how the timing of the angiogenic-to-maturation transition impacts the functionality of the established vasculature is unknown. How tissues naturally sense the correct timing for the angiogenic-to- maturation transition is also unclear, but incorporating a sensor to regulate the expression of angiogenic and maturation genes would be beneficial for creating a gene therapy with controlled dosing and minimal off-target effects. In this proposal, synthetic biology tools will be combined with engineered models of vascularization and an in vivo model of hindlimb ischemia to evaluate how the timing of angiogenic and maturation gene expression impacts functional vascular network formation and recovery from ischemia. In Aim 1, a two-channel genetic switch will be used to establish the relationship between the timing of the angiogenic-to-maturation transition and vascular network functionality. In Aim 2, hypoxia response elements will be used to generate a hypoxia-regulated genetic switch to control the induction of angiogenic and maturation genes. The genetic switch will be evaluated for its ability to rescue perfusion in an in vivo hindlimb ischemia model. The associated training plan will prepare the fellow for an academic career by enabling the fellow to obtain new skillsets in synthetic biology and in vivo models. The fellow will have many opportunities for professional development through mentoring, networking, attending conferences, and experience with grant writing. The fellow will train in the Biological Design Center at Boston University, which holds extensive expertise in molecular, cellular, and tissue engineering and presents an interdisciplinary and collaborative environment for the fellow to develop scientifically and professionally.

项目总结/文摘