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 ultimately irreversible death of cardiomyocytes. The size of a myocardial infarct correlates with the degree of deterioration of heart function, compromise of contractile reserve, and overtime the likelihood of mortality from heart failure (HF). Prompt restoration of arterial perfusion with thrombolytic and antiplatelet therapy during percutaneous coronary intervention has led to a decline in acute mortality from MI. However, the prevalence of HF among survivors has augmented, because irreversible cardiomyocyte death results in a residual inducible ischemia and permanent scarring. A major pathologic problem is the failure of human adult cardiomyocytes to regenerate themselves endogenously following a MI. This is compounded by a lack of adjunctive treatments, pharmacologic or cellular, that can be administered in conjunction with reperfusion, or after to stimulate regeneration of heart muscle. Effective promotion of endogenous cardiomyocyte regeneration in the ischemic heart with concomitant reduction of scar size would potentially offer a powerful new treatment of MI and its adverse pathophysiologic consequences. Inhibition of a specific combination of four MicroRNAs (miR); 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 miRs are conserved in humans. In vivo, adeno-associated virus (AAV) delivery of inhibitors of these miRs into the hearts of mice with left coronary artery ligation increases the expression of the beta subunit of farnesyl-transferase and SWI/SNF-related matrix associated actin-dependent regulator of chromatin subfamily a, member 5. Cardiac regeneration was confirmed by the expression of proliferation and cytokinesis markers, labeled uridine incorporation into DNA, together with scar tissue regression and heart functional improvement. A disadvantage of viral delivery is the high prevalence of anti-AAV antibodies in humans that could neutralize their effect. As an alternative, JAAN Biotherapeutics will investigate whether two synthetic, specific, potent and nuclease resistant nucleic acid miR inhibitors (anti-miRs) to miR-99/100 and let-7a/c can reduce ischemic injury in an experimental murine model of ischemic reperfusion and constitute an innovative approach to regenerate human cardiomyocytes. [The research in Phase I will define whether the anti-miRs proliferate normal heart muscle, provide information on an effective dose and sustainability of effect, and establish any proliferative or off-target side effects in remote tissues (Aim 1). Aim 2 will study whether the anti- miRs administered after a 60 min cardiac ischemic injury in mice either at the time of reperfusion or 2 days after ischemia can reduce scar size, increase cardiac function and regenerate cardiac muscle. Aim 1 will provide safety information and Aim 2 is critical to confirm efficacy of the anti-miRs in the murine ischemic heart. These studies are pivotal for future preclinical and clinical study design.]
Public Health Relevance Statement: PROJECT NARRATIVE The proposals objective is to develop a therapy that can be given to patients shortly after a heart attack to improve their long-term outcome and prevent heart failure, the single largest cause of death in the world. 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 is studying an innovative ribonucleic acid interference technology that regenerates damaged cardiac muscle by reactivating an evolutionary conserved process. In partnership we intend to test whether two synthetic [ ribonucleic nucleic acid inhibitors regenerate heart muscle without side effects and can reduce the pathophysiology of cardiac ischemic injury in mice. Information on the dose, sustainability of effect and timing of administration to regenerate heart muscle will enable the design of future safety toxicology studies, potentially allowing clinical development that may] improve the long-term outcome for patients with ischemic heart disease.
Project Terms: Actins; Acute; Acute myocardial infarction; Adult; Adverse effects; aging population; American; Animal Model; Antibodies; Arterial Fatty Streak; base; Biological Response Modifier Therapy; Biotechnology; Blood flow; Businesses; California; Cardiac; Cardiac Catheterization Procedures; Cardiac Myocytes; cardiac regeneration; Cause of Death; Cessation of life; Chromatin; Cicatrix; Clinical; clinical application; clinical development; Clinical Research; clinically relevant; Congestive Heart Failure; Coronary; Coronary artery; cost; Cytokinesis; Dependovirus; design; Deterioration; Development; Disadvantaged; DNA; Doctor of Medicine; Doctor of Philosophy; Dose; Failure; Family; Functional disorder; functional improvement; Future; Heart; Heart failure; heart function; High Prevalence; Human; Imagery; improved; in vivo; Incidence; inhibitor/antagonist; Injection of therapeutic agent; Injury; innovation; Institutes; Investigational New Drug Application; Ischemia; Label; Laboratories; Lead; Left; Legal patent; Licensing; Ligation; locked nucleic acid; Mammals; Medical; medical schools; member; Methods; MicroRNAs; Morbidity - disease rate; mortality; mouse model; Mus; muscle regeneration; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; nuclease; nucleic acid inhibitor; Nucleic Acids; Oligonucleotides; Organ; Outcome; outcome forecast; Pathologic; Patient-Focused Outcomes; Patients; percutaneous coronary intervention; Perfusion; Phase; Phase II Clinical Trials; Physiology; preclinical study; Prevalence; prevent; Probability; Procedures; Process; professor; Proliferating; protein farnesyltransferase; Proteins; Recurrence; Reperfusion Therapy; Research; Research Design; Residual state; Resistance; response; restoration; RNA; Safety; safety testing; Saline; Seaweed; Site; Staging; standard of care; Survivors; Technology; Testing; Therapeutic; Thrombus; Time; Tissues; Toxicology; Translating; translational scientist; Universities; Uridine; Viral; Woman; Zebrafish
