Our investigators advanced the field of stem cell therapy by showing that innate immune pathways are critical in the reprogramming process that changes somatic cells back to a stem-cell state, called induced pluripotent stem cells (iPSCs). We discovered that this beneficial innate immune response could be activated with small molecule agonists of TLR3 to enhance the efficiency of iPSC generation. This approach avoids integrating viral vectors, which limit therapeutic applications, and provides a method to efficiently generate therapeutic grade stem cells.
The center is developing methods for "direct reprogramming", to induce transdifferentiation of one somatic type cell into another cell type for therapeutic applications in healing. For example, fibroblasts migrate into areas of a myocardial infarction to form scars where heart tissue is damaged. If they could be transformed into endothelial cells at the site of damage, they could instead form the microvasculature needed to provide an environment that nurtures cardiac stem cells. This would improve healing with functional tissue, rather than with scar tissue.
The team is actively developing small molecules to induce human fibroblasts to transdifferentiate into endothelial cells. By combining these small molecules with nanotechnology-based delivery systems, the team is also enhancing this approach, by increasing the retention time, optimizing the specificity of targeting to damaged tissue, and improving both pharmacokinetics and pharmacodynamics by fine tuning the sustained and controlled release parameters.
The center has developed technology to rapidly and efficiently produce iPS endothelial cells (iPSC-ECs), which can generate capillaries and improve perfusion in models of peripheral arterial disease. The cells can be grown on nanopatterned collagen conduits, developed in collaboration with university and corporate partners, to produce grafts with reduced inflammation during the healing process.
In a parallel study, nanopatterned collagen threads implants have been used to generate human lymphatic iPSC-ECs to treat lymphedema, together with our corporate partner Fibralign. This work is supported by funding from the U.S. Department of Defense.
Another approach to cardiovascular regeneration is to extend the telomeric DNA, so as to increase the replicative capacity and function of the cell. The center has developed a modified mRNA approach to transiently express telomerase in human somatic and adult stem cells. This approach increases telomere length and enhances replicative capacity of the cells. Our novel mmRNA constructs were developed by Dr. Eduard Yakubov, the first to use RNA methodology to induce nuclear reprogramming. Dr. Yakubov directs the Houston Methodist Research Institute RNA Core, designated as the mmRNA core for the National Heart, Lung and Blood Institute (NHLBI) Progenitor Consortium.
Regulation of nitric oxide biology using small molecules, can be used to create clinical therapies for:
Dr. Yohannes Ghebremariam directs the nitric oxide biology laboratory in the Center for Cardiovascular Regeneration. This lab focuses on the role of nitric oxide (NO)/dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis and progression of cardiovascular and pulmonary diseases. Fundamental understanding of the endogenous and exogenous factors that influence NO/DDAH biology is critically important for the discovery and development of novel therapeutics. The lab uses throughput screening (HTS) technology to discover small molecules that regulate DDAH activity and production of NO. Small molecule activators of DDAH might have significant therapeutic potential for a number of cardiovascular diseases characterized by impaired DDAH activity and/or decreased production of NO including . By contrast, diseases characterized by overproduction of NO (principally driven by inducible NOS) and/or overly active DDAH could be therapeutically modulated by small molecule inhibitors. Examples of these diseases include.
The center is participating in the CCTRN study to pursue clinical trials in adult stem cell therapy. The study is funded by the NHLBI, and includes seven national sites. The first clinical trial will assess the utility of bone marrow derived CD34+ mononuclear cells (versus placebo) for the treatment of patients with intermittent muscle pain during exercise due to PAD. The cell therapy will be assessed for pain reduction, enhancement function, and improved blood circulation.
The center is also pursuing industry-sponsored studies to assess adult stem cell therapy for intermittent muscle pain during exercise (intermittent claudication) and blockage of blood flow to the limbs (critical limb ischemia). The clinical research arm of the center pursues opportunities to work with industry to assist in the execution of other adult stem cell trials for peripheral or coronary artery diseases.
The center produces a seminar series "Frontiers in Cardiovascular Sciences" brings internationally recognized physicians and scientists to Houston Methodist. Additional educational events in biotechnology and device development and entrepreneurship, as well as project selection for seed grants and project guidance toward licensing or company formation are also offered. The center also plans collaborative training programs, including T32 and K12 programs to support postdoctoral training, as well as mock study sessions for fellows and junior faculty who are submitting grants related to cardiovascular disease.
Sudden cardiac death from coronary heart disease occurs over 900 times per day in the United States, most often caused by ventricular fibrillation. Early CPR and defibrillation within the first 3–5 minutes after collapse, plus early advanced care, can result in high (greater than 50%) long-term survival rates. Current defibrillation methods involve external defibrillator paddles that deliver a powerful electrical shock to the heart that can be extremely painful to the patient. Dr. Miguel Valderrabano and colleagues are working to develop and test a novel method of cardiac stimulation and defibrillation that involves nanosecond megavolt pulse technology. The success of these research investigations will result in a new method of defibrillation that is more effective and less physically punishing than what is currently available.
Heart failure remains a significant public health burden, with about 5 million people in the United States afflicted and more than 600,000 deaths annually. Many studies have demonstrated that the body’s immune response and subsequent inflammation contribute to the progression of chronic heart failure. Dr. Guillermo Torre-Amione and his research team believe this to be true, and have conducted numerous studies of their own that confirm this finding and suggest novel immune modulatory therapies. Dr. Torre–Amione led the first two FDA–approved trials of Celacade, an outpatient procedure that aims to reduce inflammatory mediators in the patient’s blood, with impressive results. A Phase III trial is underway.
Platelet aggregation plays an important role in acute coronary syndromes, and contributes to the common complications associated with surgical and catheterization procedures. Understanding multiple functional aspect of platelets, the signaling pathways that regulate them, and potential abnormalities and their response to therapies are the primary objectives of Dr. Neal Kleiman and his research team. Dr. Kleiman and his team conduct important studies into investigational and FDA–approved drugs to understand the mechanisms underlying a drug’s effects and what additional factors could decrease or increase drug efficacy and safety.