Ischemic heart disease (IHD) is the single largest cause of death worldwide. A heart attack or myocardial infarction (MI) results from limitation of coronary blood flow to the heart, causing ischemia and irreversible death of cardiomyocytes. The ultimate size of an infarct correlates with the degree of deterioration of heart function, compromise of contractile reserve, and the likelihood of mortality from heart failure (HF). Prompt restoration of arterial perfusion with thrombolytic and antiplatelet therapy during percutaneous coronary interventions has led to a decline in acute mortality from MI. However, the prevalence of HF among survivors has been augmented, because irreversible cardiomyocyte death results in residual ischemia and myocardial scarring causing left ventricular dysfunction. The failure of human adult cardiomyocytes to regenerate themselves endogenously, and couple successfully with surviving myocardium following an infarction, constitutes a major clinical problem. This is compounded by the lack of adjunctive treatments, pharmacologic or cellular, that can be administered in conjunction with reperfusion to successfully stimulate regeneration of heart muscle. Promotion of endogenous cardiomyocyte regeneration in the ischemic-infarcted heart, with concomitant reduction of scar size, would offer a powerful new treatment of this devastating disease and its adverse pathophysiologic consequences. Inhibition of a specific combination of four microRNAs (miR-99, miR-100, let-7a and let-7c) is a critical regulator of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. The sequences and target proteins of these four microRNAs (miRs) are conserved in humans. In vivo, adeno-associated virus (AAV) delivery of inhibitors of these miRs into the hearts of mice with a permanent MI increases cardiomyocyte regeneration which was confirmed by the expression of proliferation and cytokinesis markers, scar tissue regression and heart functional improvement. JAAN Biotherapeutics L.L.C. has developed an optimized, single virus formulation, JBT-miR2 that simultaneously expresses inhibitors to miR-99/100 and let-7a/c. Use of this AAV2, cross packaged into AAV9 capsids (AAV2/9) allows for temporal expression, cardiac tropism, and is non integrative, minimizing potential off-target side effects. JBT-miR2 constitutes an innovative approach for regeneration of human cardiomyocytes. The proposed research in Aim 1 of this Phase I study will determine whether JBT-miR2 can regenerate murine heart muscle after a transient 60 minute ischemic injury when administered intravenously either immediately after reperfusion or one week after reperfusion. [Aim 2 will establish cardiac and tissue distribution of the virus, off-target histopathology, pleiotropic effects, metabolic function blood tests and electrophysiological changes.] Aim 1 is critical to confirm efficacy and timing of delivery of JBT-miR2 to promote cardiomyocyte regeneration. Whereas Aim 2 provides information on the safety of the virus. These studies are pivotal for future preclinical and clinical study design.
Public Health Relevance Statement: PROJECT NARRATIVE This proposal aims to develop a therapy that can be given to patients shortly after a heart attack, to improve their long-term outcome and reduce their transition to heart failure. The academic partner has developed mouse models of ischemic heart disease and methods that provide precise three-dimensional visualization and quantification of heart damage and function. The small business partner has designed and patented an innovative viral delivery approach that regenerates damaged cardiac muscle by reactivating an evolutionary conserved process. Together we will determine whether a new therapy, [JBT-miR2] can feasibly reduce the pathophysiology of ischemic injury in mice when administered intravenously and without inducing side effects. This will enable the design of future efficacy and safety toxicology studies allowing clinical development that could improve the long-term outcome for patients with ischemic heart disease.
Project Terms: Acute; Acute myocardial infarction; Adult; Adverse effects; Age; American; Amputation; Animal Model; Anterior Descending Coronary Artery; Arterial Fatty Streak; base; Biological Response Modifier Therapy; Blood flow; Blood Tests; Businesses; California; Capsid; Cardiac; Cardiac Catheterization Procedures; Cardiac Myocytes; cardiac regeneration; Cause of Death; Cessation of life; Cicatrix; Clinical; clinical application; clinical development; Clinical Research; clinically relevant; Congestive Heart Failure; Coronary; Cytokinesis; Dependovirus; design; Deterioration; Development; Dimensions; Direct Costs; Disease; Doctor of Medicine; Doctor of Philosophy; Down-Regulation; Drug or chemical Tissue Distribution; Effectiveness; efficacy testing; Electrophysiology (science); experience; Facilities and Administrative Costs; Failure; Formulation; Functional disorder; functional improvement; Future; healing; Heart; Heart failure; heart function; Histologic; Histopathology; Human; human disease; Imagery; improved; in vivo; Industrialization; Industry; Infarction; inhibitor/antagonist; Injection of therapeutic agent; Injury; innovation; Institutes; Intravenous; intravenous administration; Investigational New Drug Application; Investigational Therapies; Ischemia; Laboratories; Left; Left Ventricular Dysfunction; Legal patent; Ligation; Mammals; Medical; medical schools; Metabolic; Methods; MicroRNAs; Modeling; Morbidity - disease rate; mortality; mouse model; Mus; muscle regeneration; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; novel therapeutics; Outcome; outcome forecast; Patient-Focused Outcomes; Patients; percutaneous coronary intervention; Perfusion; Pharmacology; phase 1 study; Phase II Clinical Trials; Physiology; pleiotropism; Population; preclinical study; Prevalence; Probability; Procedures; Process; professor; Proteins; Recurrence; Regenerative response; Reperfusion Therapy; Research; Research Design; Residual state; restoration; Safety; Seaweed; Site; standard of care; Survivors; Technology; Thrombus; Time; Tissues; Toxicology; Translating; translational scientist; Tropism; Universities; Viral; Virus; Woman; Zebrafish
