Cardiac stem cells for cardiac repair
Inventors
Assignees
University of Maryland Baltimore
Publication Number
US-12156891-B2
Publication Date
2024-12-03
Expiration Date
2035-05-14
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Abstract
Embodiments of the disclosure concern compositions and methods of use related to particular c-kit+ mesenchymal cells, including cardiac stem cells, obtained from a pediatric or neonatal individual. In specific embodiments, the cells, or conditioned medium or partial or total secretomes thereof, are provided in an effective amount to an individual in need thereof.
Core Innovation
The invention relates to compositions and methods involving specific c-kit+ mesenchymal cells, particularly cardiac stem cells derived from pediatric or neonatal individuals. These cells, their conditioned medium, or the secretome (including exosomes), are provided in an effective amount for administration to individuals with cardiac medical conditions. The invention encompasses pharmaceutical compositions comprising these human cardiac cells characterized by features such as c-kit+, CD90+, CD105+, CD31−, CD34−, CD45−, and tryptase negative profiles.
The problem addressed is the need for effective compositions and methods to regenerate functional myocardium in individuals suffering from cardiac medical conditions like heart failure due to damaged myocardial tissue. While previous studies suggested the benefit of resident cardiac stem cells for myocardial repair, the differentiation of these cells into new cardiomyocytes is infrequent, indicating that other mechanisms are responsible for their regenerative capabilities. Thus, improved approaches are needed for myocardial regeneration and remodeling in both adult and pediatric patients.
This innovation provides the therapeutic use of human cardiac stem cells, especially those derived from the myocardium of neonatal or pediatric individuals. These cells exhibit regenerative or remodeling capacity upon administration, potentially through direct effects or by facilitating endogenous tissue repair. The cells can be manipulated to express or secrete beneficial factors, including VEGF-A, HGF, SCF, SDF-1α, ANG-1, and various heat shock proteins, enhancing their ability to promote cardiac repair by paracrine mechanisms.
Additionally, the invention includes methods of isolating such cells and delivering them or their secreted products (and exosomes) to individuals suffering from conditions such as heart failure, cardiomyopathy, or congenital heart disease. The pharmaceutical compositions may be formulated with pharmaceutically acceptable carriers and can be administered alone or in combination with agents that boost cellular therapeutic effects, such as heat shock response inducers.
Claims Coverage
There is one independent claim that sets out the main inventive features of this invention.
Pharmaceutical composition with genetically-engineered human neonatal cardiac stem cells
The inventive feature is a pharmaceutical composition comprising genetically-engineered, human, neonatal cardiac stem cells and one or more pharmaceutically acceptable carriers, wherein: - The stem cells are positive for protein expression of c-kit and Nkx2.5. - The stem cells are negative for protein expression of GATA4, CD31, and Isl1. - The stem cells comprise an exogenous nucleic acid construct that encodes SDF-1a, VEGF-A, PDGF-A, IL-6, or FGF-2. This feature encompasses the specific combination of phenotype (marker expression) and genetic engineering for the production of select paracrine factors relevant to cardiac repair.
The claim coverage centers on a pharmaceutical composition containing human neonatal cardiac stem cells engineered to express specific paracrine factors, defined by a distinct combination of protein markers and an exogenous nucleic acid construct. It details the cell phenotype and genetic modification as the main inventive features.
Stated Advantages
Neonatal c-kit+ cardiac stem cells demonstrate a stronger regenerative ability compared to adult derived cells due to a more potent secretome.
Cells expressing mesenchymal stem cell markers have the innate ability to be immunologically privileged, reducing immune rejection risk in allogeneic transplantation.
The invention facilitates or enhances myocardial regeneration or remodeling, improving cardiac function and reducing scar size.
Conditioned medium or exosomes from the neonatal c-kit+ cells can induce functional recovery and neovascularization in infarcted myocardium as effectively as cell transplantation.
The use of secretome components (including exosomes) enables recovery and repair of damaged myocardium even when engraftment of transplanted cells is minimal.
Heat shock response inducers can enhance the secretome and reparative potential of the cardiac stem cells.
Documented Applications
Treatment of heart failure, including congestive heart failure, by regenerating or remodeling damaged myocardium.
Therapy for cardiomyopathy, including both ischemic and non-ischemic causes.
Treatment or reversal of congenital heart disease in neonatal or pediatric individuals.
Prevention of ventricular remodeling after myocardial injury.
Regenerative treatment for damaged myocardial tissue following myocardial infarction.
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