Gene therapy encoding cell cycle factors to treat chronic ischemic heart failure in rats

• Published in: Cardiovascular research 2024-03, Vol.120 (2), p.152-163
• Main Authors: Abouleisa, Riham R E, Tang, Xian-Liang, Ou, Qinghui, Salama, Abou-Bakr M, Woolard, Amie, Hammouri, Dana, Abdelhafez, Hania, Cayton, Sarah, Abdulwali, Sameeha K, Arai, Momo, Sithu, Israel D, Conklin, Daniel J, Bolli, Roberto, Mohamed, Tamer M A
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle; Chronic Disease; Genetic Therapy; Heart Failure; Myocardial Ischemia; Myocytes, Cardiac; Rats; Swine
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvae002

Abstract Aims Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential to treat subacute ischaemic heart failure (IHF) but have not been tested in the more relevant setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective in inducing CM cell cycle re-entry and ameliorating subacute IHF models and preventing the subsequent IHF-induced congestions in the liver, kidneys, and lungs in rats and pigs. Here, we aim to test the long-term efficacy of TNNT2-4Fpolycistronic-NIL in a rat model of chronic IHF, a setting that differs pathophysiologically from subacute IHF and has greater clinical relevance. Methods and results Rats were subjected to a 2-h coronary occlusion followed by reperfusion; 4 weeks later, rats were injected intramyocardially with either TNNT2-4Fpolycistronic-NIL or LacZ-NIL. Four months post-viral injection, TNNT2-4Fpolycistronic-NIL–treated rats showed a significant reduction in scar size and a significant improvement in left ventricular (LV) systolic cardiac function but not in the LV dilatation associated with chronic IHF. A mitosis reporter system developed in our lab showed significant induction of CM mitotic activity in TNNT2-4Fpolycistronic-NIL–treated rats. Conclusion This study demonstrates, for the first time, that TNNT2-4Fpolycistronic-NIL gene therapy induces CM cell cycle re-entry in chronic IHF and improves LV function, and that this salubrious effect is sustained for at least 4 months. Given the high prevalence of chronic IHF, these results have significant clinical implications for developing a novel treatment for this deadly disease.