EP-4180050-B1 - IMMORTALIZED CARDIAC STEM CELLS FOR CARDIAC REPAIR

Inventors

• MISHRA, Rachana
• KARATHANASIS, SOTIRIOS K.
• KAUSHAL, SUNJAY
• SHARMA, Sudhish

Dates

Publication Date

20260513

Application Date

20201113

Claims (4)

1. A pharmaceutical composition for use in wound healing and / or treating a cardiac medical condition, the composition comprising a conditioned medium from one or more immortalized, human, neonatal cardiac stem cells, wherein the cells are positive for protein expression of CD117, CD105, CD90, CD73, CD47, and CD44, and negative for protein expression of CD31 and CD45, and the pharmaceutical composition comprises IGF-1, ANG-1, HGF, SDF-1α, VEGF-A, bFGF, PDGF-B, and SCF and one or more pharmaceutically acceptable carrier, excipients, diluent, surfactant, and/or vehicles.
2. The pharmaceutical composition for use of claim 1, wherein the cardiac medical condition is heart failure, cardiomyopathy, myocardial infarction, cardiac fibrosis, or congenital heart disease.
3. The pharmaceutical composition for use of claim 1 or 2, for use in repairing or remodeling myocardial tissue in a subject in need thereof.
4. The pharmaceutical composition for use of claim 1 for use in wound healing.

Description

TECHNICAL FIELD The field of the disclosure concerns at least the fields of cell biology, molecular biology, and medicine, including cardiology. BACKGROUND Heart disease in adults is a leading cause of death and there is an increasing number of children with heart failure owing to advances in surgical techniques for congenital heart defects and post-operative ICU care (Go et al., 2014; Go et al., 2014). Two of the important biological processes known to contribute to a wide range of medical conditions, including many of the underlying causes of heart disease, include inflammation and fibrosis. For centuries it was thought that, in contrast to other tissues like the liver and skin, the heart was a terminally differentiated organ unable to regenerate (reviewed in Buja 2019). This paradigm was overturned recently when it was shown that cardiomyocytes in the adult human heart turn over and are replaced at a small but detectable rate of about 1-2% per year (reviewed in Vujic et al. 2019). This motivated academics and pharmaceutical companies alike to identify and target basic mechanisms of cardiac regeneration for the treatment of various heart diseases. There are two possible mechanisms for cardiac regeneration: 1) cardiomyocyte replication and 2) the presence of endogenous cardiac stem cells able to proliferate and differentiate into cardiomyocytes. It is now clear that cardiomyocyte proliferation, although it occurs in specialized circumstances such as in amphibians, certain fishes, and neonatal mammals, does not contribute to cardiac regeneration in adult mammals. In contrast, it has been recently shown in clinical studies that transplantation of resident cardiac stem cells can repair/regenerate/remodel human myocardium, leading to improvements in cardiac function as indicated by improvements in ejection fraction, reduced scar size, reduced end diastolic and systolic volumes and improvements in quality of life and NYHA class (Garbern et al., 2013). A population of cardiac stem cells expressing the cell surface marker c-kit (also known as CD117) was described nearly fifteen years ago and homogenous, healthy populations of c-kit+ cells have been shown to provide anti-inflammatory and anti-fibrotic properties. Enrichment of these cells by magnetic selection of c-kit expressing cardiac cells followed by cardiac delivery of the cells in animal models of cardiac disease, such as myocardial infarction, indicated consistent improvements in cardiac function. Similar promising results were also observed in early clinical testing of these cells. However, with continuous scientific investigation of these cells, two issues became abundantly clear. First, these c-kit+ cardiac stem cells are a mixture of many different progenitor cells, most of which (~90%) are hematopoietic and endothelial cells, not cardiogenic stem cells (Vicinanza et al. 2017). Second, most of the cardiac c-kit+ cells obtained from adult human hearts are senescent, contributing very little to cardiac repair, and possibly even contributing to cardiac damage via the various inflammatory factors secreted by such senescent cells (Lewis-McDouggal et al. 2019). Accordingly, there is a need in the art for compositions and methods for treating cardiac medical conditions, such as heart failure caused by damaged myocardial tissue, and for addressing the inflammatory and fibrotic processes observed in a wide range of medical conditions. The present invention meets these needs and offers other related advantages. BRIEF SUMMARY The present application relates to a pharmaceutical composition for use in wound healing and/or treating a cardiac medical condition, the composition comprising a conditioned medium from one or more immortalized, human, neonatal cardiac stem cells, wherein the cells are positive for protein expression of CD117, CD105, CD90, CD73, CD47, and CD44, and negative for protein expression of CD31 and CD45, and the pharmaceutical composition comprises IGF-1, ANG-1, HGF, SDF-1α, VEGF-A, bFGF, PDGF-B, and SCF and one or more pharmaceutically acceptable carrier, excipients, diluent, surfactant, and/or vehicles. The present disclosure concerns methods and compositions related to particular human cardiac stem cells (hCSCs), especially neonatal cardiac stem cells (nCSCs), immortalized nCSCs (Im-nCSCs) (e.g., clonal isolates) and conditioned media produced by Im-nCSCs, for use in the treatment of medical conditions. The medical condition may be a cardiac medical condition. Although any inflammatory, fibrotic or cardiac medical condition may be treated with such compositions and methods, in specific embodiments the condition is a cardiac condition that would benefit from repairing, regenerating or remodeling cardiac muscle (myocardium). The methods and compositions may facilitate or enhance the reparative, regenerative or remodeling capacity of nCSCs. The medical condition may be an inflammatory condition or disease. The inflammatory condition or disease may