While experimental and clinical studies have shown that myocardial structure and function are consistently and reproducibly improved by stem cell therapy, the degree of benefit of existing cell therapies is usually modest and long-term efficacy of the regenerative process remains debatable due, in part, to the short-lived nature of the adoptively transferred cells. Current research has demonstrated the following effects of conventional cardiac stem cell therapy:
1) Myocardial structure and function are consistently and reproducibly improved although the degree of benefit is usually modest.
2) The vast majority of adoptively transferred stem cells are lost due to death or poor retention within hours to days after delivery.
3) Long-term efficacy of the regenerative process mediated by adoptively transferred cells remains debatable, due in part to their short-lived nature.
4) Therapeutically relevant implementation of stem cell-based myocardial repair ultimately depends upon enhancing the relatively modest regenerative effects currently observed.
Dr. Sussman has discovered that ex vivo modification or treatment of adoptively transferred stem cells significantly enhances their reparative and regenerative processes. These salutary effects occur both in the adoptively transferred cells and in the host myocardium upon reintroduction.
Akt is a nodal regulatory kinase serving to integrate signals involved in multiple cellular processes including survival, protein synthesis, metabolism, proliferation, and migration. Although survival signaling would indeed play a pivotal role in overcoming limited survival and proliferation exhibited by stem cells intended to promote cardiac repair, the multifaceted impact of altered chronic Akt activity rendered it less than ideal for the job. A better candidate survival molecule would promote cellular survival and proliferation without inhibiting lineage commitment and differentiation provided by appropriate environmental cues. Downstream of nuclear Akt signaling, we have identified the kinase responsible for cardioprotection named Pim-1. Unlike native Akt regulated by phosphorylation, Pim-1 is constitutively activated and is produced in response to stress or pathologic injury in the myocardium. Pim-1 is also expressed in stem cells as well as in endothelial and vascular smooth muscle cells. Primary downstream targets of Pim-1 are molecules responsible for regulation of cellular survival and mitotic activity.
CardioCreate’s approach is based upon the premise that genetic engineering of human cardiac progenitor cells (hCPCs) by Pim-1 expression will provide significant improvements over the myogenesis and regeneration currently observed with adoptive transfer approaches to treatment of myocardial damage.
The mechanistic basis of these benefits has been linked to enhanced cellular survival, secretion of beneficial paracrine factors, activation of exogenous repair processes, and contribution of donated cells to the formation of de novo myocardium. In vitro cellular studies there have shown that Pim-1 modified cardiac progenitor cells (CPCs) reproduce at an enhanced rate and possess phenotypic characteristics typical of functional myocardial cells. Studies conducted in vivo in a mouse model of myocardial infarction have revealed that these modified Pim-1 expressing CPCs, when delivered to the injured myocardium, produce functional zones of new myocardial tissue. Marker studies have shown that these new zones are supported by vascular tissue that contains cells expressing the Pim-1 gene. Furthermore, in vivo studies have shown that treated animals have a statistically significant (20%) improvement in myocardial function compared to control and this benefit is sustained for as long as 6 months. Therefore, it appears that this therapy may provide a significant step forward in the development of cell therapies for patients with MI. Based on that rationale, it is anticipated that human CPCs engineered to express Pim-1 can be developed into a cellular therapy for patients with cardiac dysfunction due to MI.