On-Demand Angiogenesis for Coronary Microvascular Disease in Women: A Synthetic Biology Approach
Abstract
This proposal addresses the FY20 PRMRP Topic Area “Women’s Heart Disease.” Heart disease is the number one cause of women’s death and disability, killing nearly 300,000 a year in the United States alone. In fact, women more likely die of heart disease than men. Coronary microvascular disease (MVD), which interrupts or stops the blood supply of small blood vessels in the heart, is one of the most dangerous forms of heart disease. MVD is more prevalent in women than men, particularly among younger women. MVD affects up to three million American women, including servicewomen and veterans, and can markedly impact patients’ quality of life. MVD impairs the physiological functions of small blood vessels that are essential to nourish working heart muscle. Because adult human heart muscle, once damaged, usually does not regenerate, MVD may lead to heart attack or heart failure, a terminal condition. Current clinical techniques were designed to treat the common heart attack and may miss the specific symptoms and pathology of MVD. MVD remains difficult for doctors to diagnose, and timely treatment may not be provided. Without treatment, MVD causes permanent damage to the heart. To address this gap, we propose a new medical technology that can detect and respond to MVD rapidly, continuously monitor the progression of MVD, and relieve the heart muscle deprived of blood supply by MVD. Synthetic biology is an emerging technology that enables precise control of human cells in a desired and beneficial manner. Using a synthetic biology approach, we aim to develop an innovative technology, the “injury-inducible synthetic gene circuit (iSGC),” to restore or replace the functionality of the impaired microvasculature (small blood vessels) in an “on-demand” manner. We hypothesize that iSGC, a man-made biological device, can encompass multiple functions needed to efficiently, effectively, and safely restore the microvascular blood flow to the endangered heart muscle. We plan to incorporate the following components into the iSGC: an artificial switch that can be quickly turned on by heart muscle injury caused by MVD, a reporter gene that releases detectable signals into the patient’s bloodstream, three biological molecules to stimulate the dilation and growth of the microvasculature to restore blood flow, and a safety switch that can turn off iSGC and prevent side effects once the demand is met. One of the three biological molecules, microRNA (miR)-29b, can effectively relieve the contraction of the microvasculature and the resulting restriction of blood flow triggered by MVD. The other two molecules, vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-B (PDGF-B), are responsible for generating new microvasculature to create new pipelines for blood supply. This is how it works: when MVD is developing in the heart, the switch in the iSGC will be turned “on,” and the iSGC will start to produce miR-29b, VEGF-A, and PDGF-B to dilate the microvasculature and stimulate its growth in the heart muscle; whereas, when the injury caused by MVD subsides, the switch will be automatically turned “off,” and the iSGC will shut down the production of all molecules to avoid side effects. Meanwhile, the reporter signals released into the bloodstream when the iSGC is turned “on” will enable doctors to monitor disease progression and the efficacy of iSGC treatment. We expect the iSGC to solve a major challenge in women’s health. Our goal is to safely and reliably implant iSGC into a patient’s heart muscle cells and have iSGC opportunely control the dilation and growth of small blood vessels only when MVD causes a demand. The heart muscle cells implanted with the iSGC will remain silent in the absence of a demand, to ensure an appropriate response. The capacity of the iSGC to turn itself on and off rapidly in response to small blood vessel dysfunction is a revolutionary feature that no therapy has yet achieved. Moreover, iSGC is a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110089
Entities
People
- Chien Wen Chen
Organizations
- Massachusetts Institute of Technology
- United States Army