CCN3 and CCN3 peptides and analogs thereof for therapeutic use
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-12024544-B2
Publication Date
2024-07-02
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 invention relates to the therapeutic use of CCN3 proteins, CCN3 analogs, and CCN3-derived peptide fragments or their analogs for treating human pathologies. These agents include native full-length CCN3 proteins, analog full-length CCN3 proteins where native cysteine residues are replaced with alternative amino acids, native CCN3 peptide fragments of about 12 to 20 amino acids, and peptide analogs with substituted cysteine residues, as well as combinations of these molecules. The invention specifically identifies peptides that mimic or improve upon the anti-fibrotic and CCN2-inhibitory activities of native CCN3.
The primary problem being addressed is the treatment and prevention of diseases associated with the overexpression of CCN2, such as fibrosis, wound healing complications, and cancer. These conditions are characterized by the over-accumulation or dysregulation of extracellular matrix proteins, with CCN2 acting as a downstream mediator in their pathogenesis. Current therapies do not effectively target these pathways without undesirable effects, and while full-length CCN3 was known to have some anti-fibrotic effects, smaller peptides with comparable or improved efficacy had not been identified.
By isolating and testing specific CCN3-derived peptides and their analogs, particularly those in the range of 12 to 20 amino acids with replaced cysteines, the invention demonstrates that certain peptides, such as CCNp37 and CCNp38, can effectively inhibit CCN2 function, block collagen accumulation, and prevent pathological cellular transitions associated with fibrosis, scarring, and cancer. These peptides are more easily produced and formulated for delivery than full-length proteins, and retain or improve upon the biological activity required for therapeutic intervention in multiple disease states.
Claims Coverage
There are two independent claims in this patent, each directed to peptides defined by specific sequences and their combinations.
Peptides comprising specific CCN3-related sequences
A peptide comprising a sequence selected from the group consisting of SEQ ID NOs: 39, 40, 59, 60, 61, and 62. These sequences define unique CCN3 or analog peptides with potential therapeutic activity.
Peptides defined by a broader set of CCN3-derived sequences and combinations
A peptide comprising a sequence selected from SEQ ID NOs: 36-40, 42, 53-62, and combinations thereof. This feature broadens the scope to include multiple specific peptide fragments, analogs, and possible mixtures for therapeutic use.
The inventive features of the claims focus on specific CCN3 and CCN3-analog peptides defined by precise amino acid sequences, covering both individual peptides and combinations for therapeutic applications.
Stated Advantages
Short CCN3-derived peptides and their analogs can mimic or improve the anti-fibrotic and CCN2-inhibitory activity of full-length CCN3 with equal or greater efficacy.
The peptides are far smaller than full-length or larger protein fragments, making them more readily synthesized and formulated for delivery.
These agents are effective at treating diseases involving over-accumulation or dysregulation of extracellular matrix, including fibrosis, scarring, wound healing, and cancer.
Peptides with substituted cysteine residues can avoid circularization and preserve or enhance biological activity.
The peptides can be customized in size or sequence to optimize therapeutic effect without loss of activity.
Documented Applications
Treatment and prevention of fibrosis, sclerosis, and scarring in organs such as kidney, heart, liver, lungs, vasculature, skin, cervix, endometrium, eye, gums, brain, and peritoneum.
Therapy for renal diseases, including diabetic nephropathy and chronic kidney disease.
Treatment of cancers, including limiting the growth of chronic myelogenous leukemia cells and potentially other cancers where CCN2 is implicated.
Improvement of wound healing and reduction of scarring, including applications for post-surgical wounds and genetic severe scarring such as keloids.
Treatment of skin fibrotic diseases such as nephrogenic systemic fibrosis.
Prevention or treatment of liver diseases including steatosis, hepatitis, and liver fibrosis.
Prevention or treatment of cardiac fibrosis and related cardiac disorders, including those secondary to diabetes or chronic kidney disease.
Therapeutic modulation of extracellular matrix disorders involving abnormal collagen deposition.
Treatment of neuroinflammation and pain through inhibition of matrix metalloproteinases by mimicking CCN3 activity.
Addition to stem cell formulations for generation of therapeutic stem cells ex vivo or for enhanced in vivo recovery from injury and fibrotic diseases.
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