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Publication Number
US-11179479-B2
Publication Date
2021-11-23
Expiration Date
Abstract
Compositions and methods for promoting adult mammalian cardiomyocytes processes and systems for enhancing cardiomyocyte regeneration are described. The invention relates to locally administering a therapeutic agent containing a modified messenger RNA for expressing a mutated serum response factor polypeptide and a modified messenger RNA for expressing a mutated YAP polypeptide into diseased heart muscle to promote cardiomyocyte proliferation and cardiac regeneration.
Core Innovation
The invention provides compositions and methods for locally administering a first modified messenger RNA for expressing a mutated serum response factor polypeptide SRF-153(A3) and a second modified messenger RNA for expressing a mutated YAP polypeptide to diseased heart muscle. The delivery uses a delivery agent such as a lipid nanoparticle or liposome, and is directed to promoting cardiomyocyte regeneration and cardiac repair and regeneration in a subject.
The invention links SRF MADS-box cofactor recruitment and Hippo/YAP signaling to cardiomyocyte de-differentiation and proliferation, using mutated SRF-153(A3) together with a mutated YAP polypeptide. The background-described problem is cardiac muscle damage, including myocardial infarction, and the need for inducing cardiomyocyte regeneration and promoting cardiac repair and regeneration.
Documented findings in vitro and in vivo are described for mRNA co-delivery. mRNA co-delivery increases DNA replication and is associated with upregulation of stem cell and cell-cycle gene clusters while downregulating cardiac differentiation/sarcomeric genes.
After myocardial infarction, local delivery into infarct border areas is described as improving functional outcomes, including enhanced LV ejection fraction and fractional shortening, with reduced infarct zone and wall thinning, with assessment by echocardiography and histology.
Claims Coverage
The independent claims cover co-delivery of two modified messenger RNAs for cardiomyocyte regeneration and cardiac repair and regeneration, using lipid nanoparticle delivery and, in one claim, injection adjacent to an identified cardiac muscle damage site. The main inventive features are centered on modified mRNAs encoding mutated SRF-153(A3) and mutated YAP polypeptides, including YAP1(5SA).
Co-preparing and co-delivering modified mRNAs for mutated SRF-153(A3) and mutated YAP
A method of inducing cardiomyocyte regeneration comprising preparing a first modified messenger RNA for expressing a mutated serum response factor polypeptide SRF-153(A3), preparing a second modified messenger RNA for expressing a mutated YAP polypeptide, and delivering the first and second modified messenger RNAs.
Lipid nanoparticle delivery into heart tissue
Delivering the first and second modified messenger RNAs using a lipid nanoparticle into a heart tissue of a subject.
Injecting an effective amount of a therapeutic composition into a heart tissue site
A method for promoting cardiac repair and regeneration in a subject comprising injecting an effective amount of a therapeutic composition into a site of a heart tissue of the subject.
Therapeutic composition containing SRF-153(A3) and mutated YAP mRNAs with lipid nanoparticle delivery
The therapeutic composition comprises a first modified messenger RNA for expressing a mutated serum response factor polypeptide SRF-153(A3), a second modified messenger RNA for expressing a mutated YAP polypeptide, and a lipid nanoparticle for delivering the first and second modified messenger RNAs into the heart tissue.
Identifying cardiac muscle damage and injecting adjacent to the damage
A method for promoting cardiac repair and regeneration in a subject comprising identifying a site of cardiac muscle damage in a heart of the subject and injecting a therapeutic composition containing both a messenger RNA for SRF-153(A3) and YAP1(5SA) into an injection site in the heart adjacent the site of cardiac muscle damage.
The independent claims collectively require co-delivering modified messenger RNAs encoding mutated SRF-153(A3) and a mutated YAP polypeptide, including YAP1(5SA), into heart tissue using lipid nanoparticles, with at least one independent claim further requiring injection adjacent to an identified cardiac muscle damage site.
Stated Advantages
Inducing cardiomyocyte regeneration.
Promoting cardiac repair and regeneration.
Increasing DNA replication.
Upregulating stem cell and cell-cycle gene clusters while downregulating cardiac differentiation/sarcomeric genes.
Improving functional outcomes after myocardial infarction, including enhanced LV ejection fraction and fractional shortening.
Reducing infarct zone and wall thinning after myocardial infarction.
Documented Applications
Local administration into diseased heart muscle for cardiomyocyte regeneration and cardiac repair and regeneration.
Treatment following myocardial infarction with delivery into infarct border areas and functional assessment by echocardiography and histology.
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