Methods for inducing cell division of postmitotic cells
Inventors
Mohamed, Tamer M. A. • Srivastava, Deepak
Assignees
Publication Number
US-11541102-B2
Publication Date
2023-01-03
Expiration Date
2036-04-05
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Abstract
The present disclosure provides methods for inducing cell cycle reentry of postmitotic cell. The present disclosure further provides cells and compositions for treating diseases, such as cardiovascular diseases, neural disorders, hearing loss, and diabetes.
Core Innovation
The invention provides methods for inducing proliferation and/or cell cycle reentry of postmitotic cells by contacting them with an effective amount of compositions comprising at least one cyclin-dependent kinase (CDK) and at least one cyclin, or equivalents thereof. This approach enables the proliferation of cells that typically have no or extremely limited proliferative capacity, including cardiomyocytes, neurons, pancreatic cells, hair cells, and skeletal muscle cells. The methods may involve genetic modification to overexpress combinations such as CDK1 and CCNB1, CDK4 and CCND1, or all four, often delivered via viral vectors or nucleic acids, and may be combined with CDK activators or transforming growth factor β inhibitors.
The problem addressed is that many adult cells like cardiomyocytes and neurons are postmitotic and unable or limited in their ability to divide and regenerate. This restriction severely limits the repair and restoration of function in organs after injury. Current regenerative medicine approaches, especially those relying on stem cells, face limitations due to declining proliferative capacity as cells age. There is a need for methods to reinitiate postmitotic cell division to enable regeneration, both for in vitro applications and in vivo treatment of diseases.
Claims Coverage
There is one independent claim in the patent, which focuses on a method of treating myocardial infarction using specific factors and their delivery methods.
Method of treating myocardial infarction with specific cell cycle regulators
A method comprising administering effective amounts of cyclin-dependent kinase-1 (CDK1), cyclin B1 (CCNB1), cyclin-dependent kinase-4 (CDK4), and cyclin D1 (CCND1) to a subject in need thereof for treatment of myocardial infarction.
Administration of genetic material via viral vectors
Administering a viral vector comprising polynucleotides encoding CDK1, CCNB1, CDK4, and CCND1, either in a single vector or two separate vectors, to deliver the therapeutic factors.
Use of transforming growth factor beta inhibitors to enhance treatment
Administering an effective amount of a transforming growth factor beta (TGF-β) inhibitor, including specifically SB431542 or dexamethasone, in the myocardial infarction treatment method.
Promotion and assay of cardiac cell proliferation
The method promotes cardiac cell proliferation, which can be assayed by increases in phosphor-histone H3 (PHH3) staining or 5-ethynyl-2′-deoxyuridine (EdU) staining of cardiac troponin T positive cells.
Improvement of cardiac structural and functional metrics
The method decreases scar size after myocardial infarction and decreases the decrease in ejection fraction (EF), thereby improving cardiac function.
Composition comprising polynucleotides encoding specific cell cycle regulators
A viral vector comprising polynucleotides encoding CDK1, CCNB1, CDK4, and CCND1 for delivering cell cycle regulators.
The independent claim and dependent claims specify methods and compositions for treating myocardial infarction by administering cell cycle regulators CDK1, CCNB1, CDK4, and CCND1 through viral vectors, optionally combined with TGF-β inhibitors, resulting in promotion of cardiac cell proliferation and improved cardiac function.
Stated Advantages
Inducing proliferation and/or cell cycle reentry in postmitotic cells increases regenerative capacity of tissues with limited repair abilities.
Overexpression of CDK1, CCNB1 and AURKB promotes cardiac cell proliferation and functional improvement post-myocardial infarction.
Combinatorial use of CDK1/CCNB1/CDK4/CCND1 cocktails enhances proliferation and survival of human postmitotic cardiomyocytes more effectively.
Use of TGF-β inhibitors enhances cell survival during induction of proliferation.
Improved cardiac function and reduced scar size in animal models following treatment with the compositions.
Documented Applications
Treatment of cardiovascular diseases including myocardial infarction (heart attack), ischemic heart conditions, cardiomyopathies, heart failure, and related cardiac disorders by inducing proliferation of cardiomyocytes.
Treatment of neurological diseases such as spinal cord injury, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and stroke by inducing proliferation of neural cells.
Treatment of pancreatic diseases including diabetes mellitus and pancreatitis by inducing proliferation of pancreatic beta cells.
Treatment of hearing loss due to various causes by inducing proliferation of hair cells in the inner ear.
Methods to increase skeletal muscle mass in muscle diseases or for muscle building by inducing proliferation of skeletal muscle cells.
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