CCN3 and CCN3 peptides and analogs thereof for therapeutic use
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-11505582-B2
Publication Date
2022-11-22
Expiration Date
2031-04-04
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Abstract
The present invention provides a method for treating a human patient with a pathology by administering to the subject an effective amount of an agent selected from the group of: native full-length CCN3 proteins; analog CCN3 full-length proteins with native cysteine residues substituted by a replacement amino acid; CCNp native peptide fragments having from about 12 to about 20 amino acids; analog CCNp peptide fragments with native cysteine residues substituted with a replacement amino acid; and combinations thereof.
Core Innovation
The present invention provides a method for treating a human patient with a pathology by administering an effective amount of a CCN3 agent, including native full-length CCN3 proteins, analogs with native cysteines replaced by a different amino acid, native CCN3 peptide fragments of about 12 to 20 amino acids, analogs of these fragments with cysteine substitutions, or combinations thereof. These agents are designed to mimic or enhance the anti-fibrotic activity of CCN3, blocking fibrosis or scar development, and are intended for treating cancer and other disease processes involving CCN2 and CCN3.
The invention addresses diseases associated with the overexpression of CCN2, such as fibrosis, wound healing, and cancer. CCN2 has been shown to promote fibrosis, and the inventors have discovered that full-length CCN3 and specifically identified short CCN3-derived peptides (including analogs with cysteine replaced by serine or other amino acids) demonstrate significant activity in down-regulating CCN2, thus preventing abnormal accumulation of extracellular matrix (ECM) molecules like collagen, which underlie fibrotic disease.
Through selection and screening of short overlapping peptides derived from CCN3, including both native and analog versions, the inventors found specific peptides—such as CCNp37 and CCNp38—that effectively inhibit CCN2-mediated processes, such as collagen promoter activation, cellular adhesion, and the phenotypic transition involved in fibrosis. These small peptides are more easily manufactured and formulated compared to full-length proteins and can be therapeutically applied to treat or prevent disorders mediated by ECM dysregulation, especially those involving CCN2.
Claims Coverage
There are two independent claims, each defining distinct inventive features regarding CCN3 peptides and their therapeutic use.
CCN3 peptide compositions comprising specific sequences
The invention provides a CCN3 peptide comprising a sequence selected from SEQ ID NOs: 36, 37, 38, 42, 49, 50, 53, 54, 55, 56, 57, 58, and 60. These include both native and analog CCN3 peptide sequences, enabling targeted peptide-based therapies derived from defined regions of the CCN3 molecule.
Therapeutic method using CCN3 peptides for diseases of ECM and inflammation
A method for treating fatty liver disease, steatosis, liver fibrosis, liver cancer, hepatitis, inflammation, or neural inflammation in a subject by administering an effective amount of a CCN3 peptide comprising a sequence selected from SEQ ID Nos: 36-38, 40, 42, 49-50, 53-58, 60, and combinations thereof. This covers the use of specified CCN3 short peptides as therapeutic agents across a spectrum of diseases involving fibrosis, cancer, or inflammation processes.
The claims secure patent coverage for CCN3-derived peptides of specific sequences and their use in treating a broad range of fibrotic, cancerous, and inflammatory diseases.
Stated Advantages
CCN3 peptides and their analogs can mimic or exceed the anti-fibrotic activity of full-length CCN3 proteins in regulating CCN2 and extracellular matrix protein expression.
Short CCN3-derived peptides are far smaller than full-length proteins, making them more easily synthesized and formulated for therapeutic delivery.
The peptides can specifically block CCN2 synthesis and activity, cellular adhesion to CCN2, collagen accumulation, and cell phenotypic transition to fibroblast-type cells, thereby preventing fibrosis and scarring.
Certain peptides demonstrated dose-dependent efficacy, specificity, and versatility in treating multiple disease models both in vitro and in vivo.
Documented Applications
Treatment of fibrosis, sclerosis, and scarring in organs including kidney, heart, liver, lungs, vasculature, skin, cervix, endometrium, eye, gums, brain, and peritoneum.
Reduction or prevention of abnormal wound healing including skin scarring, keloids, and post-surgical scarring.
Treatment of cancers, specifically for limiting growth or proliferation of human chronic myelogenous leukemia cells.
Therapy for fatty liver disease, steatosis, hepatitis, liver fibrosis, and liver cancer.
Blockade of cell proliferation, matrix metalloproteinase (MMP-1) production, and tissue inhibitor of metalloproteinase (TIMP-1), as related to processes in ECM accumulation and turnover.
Treatment or prevention of cardiac fibrosis and cardiac hypertrophy in the context of diabetic and renal disease.
Reduction of neural inflammation and pain by modifying inflammatory mediator profiles and matrix metalloproteinase expression.
Use in stem cell therapy formulations to generate or condition therapeutic stem cells ex vivo for treatment of fibrosis, cancer, multiple sclerosis, and cystic fibrosis.
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