Epicardial-derived paracrine factors for repairing cardiac tissue
Inventors
Ruiz-Lozano, Pilar • Mercola, Mark • Wei, Ke
Assignees
Regencor Inc • Sanford Burnham Prebys Medical Discovery Institute
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Publication Number
US-10682416-B2
Publication Date
2020-06-16
Expiration Date
Abstract
Provided herein, inter alia, are compositions and kits comprising epicardial-derived paracrine factors (such as, hypoglycosylated follistatin-like 1 (FSTL1)) for treating and repairing damage to cardiac tissue caused by cardiovascular disease, myocardial infarction (MI), other ischemic events, or cardiac-growth deficiency, as well as methods for using the same.
Core Innovation
The invention relates to repairing cardiac tissue following injury in a subject by contacting the cardiac tissue with a hypoglycosylated follistatin-like 1 (FSTL1) polypeptide. The hypoglycosylated FSTL1 lacks N-linked glycosylation at one or more glycosylation-competent asparagine residues, or comprises substitution of one or more glycosylation-competent asparagine residues with glycosylation-incompetent residues. The repair is linked to hypoglycosylated FSTL1 as the functional paracrine factor delivered to injured cardiac tissue.
The disclosed approach addresses myocardial injury associated with ischemia-reperfusion, ischemic heart disease, hypoplastic heart injury, and/or myocardial infarction, where the heart optionally contains scar tissue. The treatment is described as epicardial-derived paracrine therapy and is associated with cardiac functional recovery and tissue regeneration outcomes. The disclosure further reports changes associated with cardiomyocyte cell-cycle entry and cytokinesis markers, including Aurora B kinase and phospho-Histone H3.
The document connects the reparative outcomes to the glycosylation status of FSTL1, distinguishing hypoglycosylated or unglycosylated forms from glycosylated forms. Hypoglycosylated FSTL1 is reported to promote proliferation in immature cardiomyocytes, while glycosylated forms are reported to be cardioprotective and anti-apoptotic but non-proliferative. The disclosure further states that hypoglycosylated FSTL1 does not activate Akt-1 signaling (Akt-1 (phospho-Akt Ser473/Thr308)), and includes improved outcomes including reduced fibrosis/scar and restored vascularization.
Claims Coverage
The partial claim set includes three independent claims: a method, a sterile pharmaceutical composition, and a kit. Across these claims, the inventive subject matter centers on hypoglycosylated FSTL1 lacking N-linked glycosylation at glycosylation-competent asparagine residues, optionally formulated with pharmaceutically acceptable excipients and optionally provided with a 3D collagen patch and adhesion means.
Hypoglycosylated FSTL1 contact for repairing injured cardiac tissue
A method for repairing cardiac tissue following an injury in a subject in need thereof by contacting the cardiac tissue with a hypoglycosylated follistatin-like 1 (FSTL1) polypeptide, wherein the hypoglycosylated FSTL1 polypeptide lacks N-linked glycosylation at one or more glycosylation-competent asparagine residues, or comprises substitution of one or more glycosylation-competent asparagine residues with glycosylation-incompetent residues.
Sterile pharmaceutical composition with hypoglycosylated FSTL1 and excipients
A sterile pharmaceutical composition comprising a hypoglycosylated follistatin-like 1 (FSTL1) polypeptide and one or more pharmaceutically acceptable excipients, wherein the hypoglycosylated FSTL1 polypeptide lacks N-linked glycosylation at one or more glycosylation-competent asparagine residues, or comprises substitution of one or more glycosylation-competent asparagine residues with glycosylation-incompetent residues.
Kit with hypoglycosylated FSTL1, excipients, optional 3D collagen patch, and optional adhesion means
A kit comprising a hypoglycosylated follistatin-like 1 (FSTL1) polypeptide lacking N-linked glycosylation at one or more glycosylation-competent asparagine residues, or comprising substitution of one or more glycosylation-competent asparagine residues with glycosylation-incompetent residues; and one or more pharmaceutically acceptable excipients; optionally including a three dimensional (3D) collagen patch with optional embedding or seeding of the hypoglycosylated FSTL1 and optional elastic modulus of 12±4 kPa; and/or adhesion means for adhering the 3D collagen patch to the epicardium or to the myocardium of an injured heart, optionally comprising sutures.
Across the independent claims, the coverage is directed to repairing injured cardiac tissue using hypoglycosylated FSTL1 polypeptides defined by absent N-linked glycosylation or glycosylation-incompetent asparagine substitutions, provided as a method of contact, as a sterile pharmaceutical composition with excipients, and as a kit that may optionally include a 3D collagen patch and adhesion means.
Stated Advantages
Repairing injured cardiac tissue following injury in a subject.
Improving cardiac function.
Reducing fibrosis/scar (fibrosis area) and scar tissue.
Restoring vascularization and increasing vascular perfused area.
Inducing cardiomyocyte cell-cycle entry and cytokinesis, associated with Aurora B kinase and phospho-Histone H3 markers.
Hypoglycosylated FSTL1 does not activate Akt-1 signaling (phospho-Akt Ser473/Thr308).
Documented Applications
Repair of cardiac tissue after myocardial injury including ischemia-reperfusion injury, ischemic heart disease, hypoplastic heart injury, and/or myocardial infarction, optionally with scar tissue.
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