Transient Cell Cycle Induction in Cardiomyocytes to Treat Subacute Ischemic Heart Failure

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Gene Therapy

Background:

• Limited endogenous heart regeneration post-myocardial infarction (MI).
• Previous work demonstrated four cell cycle factors (4F) promote cardiomyocyte proliferation and improve cardiac function in mice.
• Need to understand the mechanisms and preclinical efficacy of 4F therapy.

Purpose of the Study:

• Identify reprogramming stages during 4F-induced cardiomyocyte proliferation.
• Conduct preclinical testing of 4F gene therapy for ischemic heart failure in large animal models.

Main Methods:

• Temporal single-cell RNA sequencing to analyze cardiomyocyte reprogramming.
• Development of a transient, cardiomyocyte-specific lentiviral vector (TNNT2-4Fpolycistronic-NIL).
• Intramyocardial injection of the viral vector in rat and pig MI models.

Main Results:

• 4F induced cell cycle reprogramming in 15% of cardiomyocytes, linked to metabolic changes.
• TNNT2-4Fpolycistronic-NIL treatment significantly improved ejection fraction and reduced scar size in rats and pigs.
• Sustained cardiac function improvement and absence of arrhythmias or tumorigenesis observed in rats up to 4 months post-treatment.

Conclusions:

• Mechanistic insights into forced cardiomyocyte proliferation were gained.
• A novel transient and cardiomyocyte-specific viral construct minimizes oncogenic risk.
• The study supports the clinical feasibility of 4F gene therapy for treating ischemic heart failure.