Ischemic heart disease (IHD) is the single largest cause of death in the industrialized world and contributor to the development of Heart Failure (HF) in adults 1-2. IHD can be caused by a myocardial infarction (MI), which limits 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 3, compromise of contractile reserve, and over time the likelihood of mortality from HF 4. 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 to stimulate regeneration of heart muscle and prevent the transition to HF. The effective promotion of endogenous cardiomyocyte regeneration in the ischemic heart would potentially offer a powerful new treatment for MI and its adverse pathophysiologic consequences. Inhibition of a specific combination of four MicroRNAs (miRs); miR-99, miR-100, let-7a and let-7c, is a critical regulator of cardiomyocyte dedifferentiation and proliferation in mammals 6. JBT has designed and tested an adeno associated virus known as JBT-miR2, which allows for temporal, cardiac and non-integrative expression of inhibitors to these four miRs. In preliminary studies in young mice with cardiac Ischemic Reperfusion (IR) injury the efficacy and safety of a single dose of JBT-miR2 administered by intravenous injection at the time of reperfusion was compared with Control virus. JBT-miR2 increased heart function and decreased cardiac volumes at 2-weeks post IR with a corresponding ~47% reduction in scar tissue at 8-weeks post-IR compared with control virus. To continue with Research and Development required for clinical trials it is necessary to confirm the efficacy and safety in clinically translational larger aged animals.
The Specific Aims of this Phase I SBIR grant are to: 1: Conduct a dose range finding efficacy, safety and PK study of JBT-miR2 in middle aged mini-pigs with IR injury, evaluating pleiotropic effects and mechanism of action. Significant, reproducible, clinically relevant end-point changes in measures of cardiac dimension and function are expected in JBT-miR2 treated animals compared to Control virus. 2. Develop and validate PK and in vitro bioactivity assays. Assess for immunogenicity, neutralizing antibodies, and viral particle titer levels to determine viral shedding in pigs. A Target Product Profile will be drafted, with an understanding of measures of drug product identity, activity and purity. 3. These results will allow preparation for, and conduction of a type C meeting with FDA to provide agreement on the design of a Good Laboratory Practice safety toxicology studies required for clinical translation.
The long-term objective of this proposal is to develop a therapy that can be given to patients shortly after a heart attack to prevent heart failure, which is the single largest cause of death in the world. At Jaan Biotherapeutics we have developed an innovative viral delivered treatment that re-activates pathways to promote diseased heart muscle to repair itself within the damaged organ. Having confirmed that the treatment works and is safe in mice with a heart attack, we will test the treatment in larger and older animals with a heart attack, in this case the pig, which is required before testing in people.
