CCN3 and CCN3 peptides and analogs thereof for therapeutic use
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-10351608-B2
Publication Date
2019-07-16
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 addresses diseases associated with the overexpression of CCN2, such as fibrosis, wound healing, and cancer, by providing therapeutic agents selected from native full-length CCN3 proteins, analog full-length CCN3 proteins with cysteine residues substituted by a replacement amino acid, native CCN3 peptide fragments of about 12 to about 20 amino acids, and analog peptide fragments with cysteine residues substituted. The invention further provides combinations of these agents, and discloses that CCN3 peptides and their analogs can function as substitutes for full-length CCN3 proteins, achieving equal or greater anti-fibrotic activity.
The problem being solved is the over-accumulation, disregulation of turnover, or altered composition of extracellular matrix proteins, primarily due to CCN2 overexpression, which leads to fibrosis, scarring, abnormal wound healing, and cancer cell or tumor growth. Existing solutions using full-length CCN3 proteins are limited, and there was no disclosure or evidence that smaller CCN3 fragments or peptides could mediate the same anti-fibrotic or anti-CCN2 activities, particularly as therapeutics.
The core discovery is that a small number of specific short CCN3-derived peptides and their cysteine-substituted analogs can mimic or improve upon the anti-fibrotic and anti-CCN2 effects of full-length CCN3, offering advantages in synthesis and delivery. The invention demonstrates that peptides such as CCNp37 and CCNp38—both with native and modified sequences—block CCN2 activity, collagen production, cellular adhesion to CCN2, and the phenotypic transition essential for fibrosis development. These peptides act through blockade of CCN2 synthesis and activity in vitro and in disease models.
The invention identifies routes for administration, modification for stability or targeting, and application in the prevention and/or treatment of diseases characterized by excessive extracellular matrix, such as fatty liver disease, steatosis, hepatitis, neural inflammation, and cancer. The invention further covers methods for using these peptides in stem cell treatments and for custom-tailored therapies targeting a wide range of CCN2-related pathologies.
Claims Coverage
The patent contains two independent claims, each focusing on the use of specific CCN3-derived peptides or analogs for treating defined diseases.
Treatment with selected CCN3 peptides for fatty liver disease, steatosis, hepatitis, or neural inflammation
The claimed method comprises administering to a human subject an effective amount of an agent selected from SEQ ID NOs: 48-50, 52, and 63, or combinations thereof. - The method encompasses treating fatty liver disease, steatosis, hepatitis, or neural inflammation. - The agents are specific CCN3 peptide sequences, explicitly defined by their sequence identification numbers, and cover combinations thereof.
Treatment of fatty liver disease, steatosis, liver fibrosis, or liver cancer with analog CCNp38 peptide fragment
The claimed method comprises administering to a subject an effective amount of an analog CCNp38 peptide fragment in which native cysteine residues have been substituted with a replacement amino acid. - The treatment is specifically for fatty liver disease, steatosis, liver fibrosis, or liver cancer. - The replacement amino acid is selected from serine, alanine, glycine, S-methylated cysteine, or combinations thereof. - Administration may include delivery via various routes, use of carrier molecules such as polyethylene glycol, glycol groups, proteins, or serum proteins, and further modification to enhance stability, shelf life, in vivo targeting, cell attachment, or entry.
The inventive features establish specific methods for treating liver and inflammation-related diseases using defined CCN3-derived peptides and analogs, particularly emphasizing peptides with modified cysteine residues and their therapeutic application across a broad spectrum of CCN2-related disorders.
Stated Advantages
Short CCN3-derived peptides can achieve equal or better anti-CCN2 and anti-fibrotic activity compared to full-length CCN3 proteins.
These peptides are far smaller than native or previously described CCN3 protein fragments, making them more easily synthesized and formulated for delivery.
The peptides can be modified to improve stability, shelf life, half-life in vivo, targeting, cell attachment, or entry into target cells.
The invention allows for custom-tailored therapies by selecting appropriate CCN3 peptides or analogs for the specific needs of a patient.
Peptides provide manufacturing and delivery advantages due to their small size and modifiability.
Documented Applications
Treatment of fatty liver disease, steatosis, hepatitis, and neural inflammation by administering CCN3 peptides or analogs.
Treatment of liver fibrosis and liver cancer using analog CCNp38 peptide fragments.
Use in preventing or treating fibrosis, scarring, and abnormal wound healing in organs such as kidney, heart, liver, lungs, vasculature, skin, cervix, endometrium, eye, gums, brain, and peritoneum.
Treatment of cancer, including chronic myelogenous leukemia, and reduction of cancer cell growth or metastasis.
Application in cutaneous wound healing, including reduction of skin scarring and conditions such as nephrogenic systemic fibrosis.
Treatment and prevention of cardiac fibrosis, including that associated with diabetes, chronic kidney disease, atherosclerosis, vascular calcification, and hypertrophy.
Treatment of neuroinflammation and pain, including in models of persistent inflammatory pain.
Use in ex vivo stem cell treatment formulations by conditioning stem cells with CCN3 peptides before transplantation.
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