Therapeutic agent for cardiomyopathy, old myocardial infarction and chronic heart failure
Inventors
Tamai, Katsuto • Sawa, Yoshiki • Miyagawa, Shigeru • Kido, Takashi • GOTO, Takasumi • Yamazaki, Takehiko
Assignees
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Publication Number
US-11969459-B2
Publication Date
2024-04-30
Expiration Date
Abstract
The present inventors have found that HMGB1 fragment peptides having a particular amino acid sequence exhibit the effects of improvement of cardiac function, inhibition of cardiomyocyte hypertrophy, inhibition of myocardial fibrosis, and promotion of angiogenesis in an animal model of dilated cardiomyopathy, that the particular HMGB1 fragment peptides also exhibit the effects of improvement of cardiac function, inhibition of cardiomegaly, inhibition of cardiomyocyte hypertrophy, inhibition of myocardial fibrosis, and promotion of angiogenesis in an animal model of ischemic cardiomyopathy caused by old myocardial infarction, and that the particular HMGB1 fragment peptides exhibit the effects of inhibition of cardiomyocyte hypertrophy and inhibition of myocardial fibrosis in an animal model of hypertensive cardiomyopathy. Based on these findings, pharmaceutical compositions are provided for the prevention and/or treatment of cardiomyopathy and old myocardial infarction and chronic heart failure resulting therefrom, which comprise an HMGB1 fragment peptide having a particular amino acid sequence.
Core Innovation
The invention relates to HMGB1 fragment peptides, including a peptide consisting of the amino acid sequence described in SEQ ID NO: 1, for use as pharmaceutical agents in subjects having cardiomyopathy. The method includes identifying a subject with cardiomyopathy and administering to the subject an effective amount of a selected peptide. The selected peptides include SEQ ID NO: 1 and peptides having mesenchymal stem cell migration-stimulating activity with defined amino acid sequence relationships to SEQ ID NO: 1.
The cardiomyopathy is selected from dilated cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy. The invention addresses cardiomyopathy-associated heart structural abnormality and dysfunction, where the structural abnormality is selected from cardiomegaly, cardiomyocyte hypertrophy, and myocardial fibrosis, and the dysfunction is selected from impaired contractility and impaired diastolic capacity.
The described approach is framed around stimulating migration and recruitment of mesenchymal stem cells or bone-marrow-derived cells in the heart. The documented effects include inhibition of myocardial fibrosis and cardiomyocyte hypertrophy, promotion of angiogenesis, increased CD31+ vessels and vWF staining, expression changes including VEGF and TSG-6, preservation of mitochondrial cristae, and improved cardiac function outcomes in animal models.
Claims Coverage
The partial content identifies four independent claims. Across the claims, the inventive features center on administering an effective amount of a defined HMGB1 fragment peptide family to a subject with cardiomyopathy, with separate claim sets directed to treating cardiomyopathy, inhibiting structural abnormality, promoting angiogenesis, and improving contractility or diastolic capacity.
Treating cardiomyopathy with HMGB1 fragment peptide variants
A method of treating cardiomyopathy by identifying a subject with cardiomyopathy and administering an effective amount of a peptide selected from peptides consisting of the amino acid sequence described in SEQ ID NO: 1, peptides resulting from substitution, deletion, insertion, or addition of one amino acid in the SEQ ID NO: 1 sequence with activity of stimulating migration of mesenchymal stem cells, peptides sharing 97% or more sequence identity with the SEQ ID NO: 1 sequence and having mesenchymal stem cell migration-stimulating activity, and peptides resulting from addition of one or two amino acids to the SEQ ID NO: 1 sequence with mesenchymal stem cell migration-stimulating activity.
Inhibiting heart structural abnormality in cardiomyopathy
A method of inhibiting a structural abnormality of the heart in cardiomyopathy by identifying a subject with cardiomyopathy and administering an effective amount of a peptide selected from the SEQ ID NO: 1 family, where the structural abnormality is selected from cardiomegaly, cardiomyocyte hypertrophy, and myocardial fibrosis, and cardiomyopathy is selected from dilated cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy.
Promoting angiogenesis in the cardiomyopathy heart with HMGB1 fragment peptides
A method of promoting angiogenesis in the heart in cardiomyopathy by identifying a subject with cardiomyopathy and administering an effective amount of a peptide selected from the SEQ ID NO: 1 family, where the subject has a structural abnormality selected from cardiomegaly, cardiomyocyte hypertrophy, and myocardial fibrosis and a dysfunction selected from impaired contractility and impaired diastolic capacity.
Improving contractility or diastolic capacity in cardiomyopathy with HMGB1 fragment peptide variants
A method of improving the contractility or diastolic capacity of the heart in cardiomyopathy by identifying a subject with cardiomyopathy and administering an effective amount of a peptide selected from the SEQ ID NO: 1 family, where the subject has a structural abnormality selected from cardiomegaly, cardiomyocyte hypertrophy, and myocardial fibrosis and dysfunction selected from impaired contractility and impaired diastolic capacity.
Across the independent claims, the coverage centers on administering an effective amount of HMGB1 fragment peptide SEQ ID NO: 1 and sequence-related variants that stimulate migration of mesenchymal stem cells. The claim sets differentiate therapeutic objectives as treating cardiomyopathy, inhibiting specified structural abnormalities, promoting angiogenesis, and improving contractility or diastolic capacity, within dilated, ischemic, or hypertensive cardiomyopathy.
Stated Advantages
Inhibiting a structural abnormality of the heart in cardiomyopathy.
Promoting angiogenesis in the heart in cardiomyopathy.
Improving the contractility or diastolic capacity of the heart in cardiomyopathy.
Treating cardiomyopathy.
Documented Applications
Prevention or treatment of cardiomyopathy and chronic heart failure after old myocardial infarction, including dilated cardiomyopathy and ischemic cardiomyopathy contexts.
Therapeutic use in hypertensive cardiomyopathy, including an HFpEF-like context.
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