Heart Muscle Regeneration

PROJECT SUMMARY
Ischemic heart disease (IHD) is the largest cause of death of humans. IHD can be caused by a myocardial
infarction (MI), which limits coronary blood flow to the heart, causing ischemia and irreversible death of
cardiomyocytes (CMs). The size of a myocardial 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
intervention (PCI) has decreased acute mortality from MI. However, prevalence of HF among survivors has
augmented due to irreversible CM death results in a residual inducible ischemia and permanent scarring. A major
pathologic problem is the failure of human adult CMs 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 (Rep) to stimulate regeneration of heart muscle and prevent the transition to HF.
The effective promotion of endogenous CM regeneration in the ischemic heart would potentially offer a powerful
new treatment for MI and its adverse pathophysiologic consequences. Inhibition of four specific MicroRNAs
(miRs); miR-99, miR-100, let-7a and let-7c, critically regulates CM dedifferentiation, proliferation and
redifferentiation in mammals. JBT has designed an adeno associated human viral delivered therapeutic known
as JBT-miR2-ADD, which allows for temporal, cardiac and non-integrative expression of inhibitors to these four
miRs. As part of pilot studies, five, four-month-old Yucatan female pigs were administered with an intracoronary
(IC) infusion of JBT-miR2-ADD or Control virus at Rep after a 60-min occlusion of the left coronary artery followed
by a second intravenous (IV) injection at 8-weeks with necropsy at 10-weeks. Compared to Control, JBT-miR2-
ADD increased left ventricular (LV) mass and ejection fraction and reduced LV scar tissue. Unlike other cardiac
muscle repairing therapeutics that have not been commercialized, JBT-miR2-ADD had no safety issues including
cardiac hypertrophy, arrhythmogenesis, sudden cardiac death, cardiomegaly, hyperplasia, liver or kidney toxicity
in swine and extensive murine studies. Although JBT-miR2-ADD administered by IV or IC is safe and effective
in animals, the IV route is more amenable to patients who cannot undergo PCI. [The Specific Aims of this Phase
II SBIR grant are to Aim 1- to confirm the effective dosing strategy (i.e. single dose at Rep, or 8-weeks post-IR,
or two doses at Rep and 8-weeks post-IR) to attain the required statistical improvement in efficacy] and Aim 2-
to assess the safety of JBT-miR2-ADD in both male and female Yucatan swine with IR injury. The animals will
be followed to 4-months post IR. Aim 3 will evaluate the pharmacokinetics and anti-viral neutralizing antibody
production to JBT-miR2-ADD. Aim 4 is to conduct a nine-month Good Laboratory Practice (GLP) long-term
safety study of JBT-miR2-ADD in uninjured swine. For Aim 5 a study report and a pre-Investigational New Drug
meeting will be conducted with the FDA to determine the to determine the studies required to file an IND.

Grant Number: 1R44HL180034-01A1
NIH Institute/Center: NIH
Principal Investigator: Bhawanjit Brar