Methods for using synthetic triterpenoids in the treatment of bone or cartilage diseases or conditions
Inventors
Sporn, Michael B. • Liby, Karen T. • Gribble, Gordon W. • Suh, Nanjoo • Medici, Damian • Robey, Pamela Gehron
Assignees
Dartmouth College • Rutgers State University of New Jersey • US Department of Health and Human Services
Publication Number
US-8921340-B2
Publication Date
2014-12-30
Expiration Date
2027-11-16
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Abstract
The present invention features the use of a synthetic triterpenoid to induce gene expression and differentiation of stem or progenitor cells in the treatment of bone/cartilage diseases or conditions.
Core Innovation
The invention provides methods and reagents for inducing gene expression and differentiation of stem or progenitor cells using synthetic triterpenoids to treat bone and cartilage diseases or conditions. It specifically demonstrates that synthetic triterpenoid compounds alter gene expression in stem or progenitor cells and induce their differentiation toward desired phenotypes relevant for therapeutic applications.
The method involves contacting stem or progenitor cells, such as mesenchymal stem cells, adipose tissue-derived mesenchymal stem cells, embryonic stem cells, stem cells from exfoliated deciduous teeth, periosteum cells, osteoprogenitor cells, or growth plate progenitor cells, with an effective amount of a synthetic triterpenoid. This induces the expression of one or more genes including SOX9, COL2A1, TGF-β1, TGF-β2, TGF-β3, BMP2, BMP4, BMPRII, SMAD3, SMAD4, SMAD6, SMAD7, TIMP-1, or TIMP-2, which are markers indicative of chondrogenesis and differentiation relevant to bone and cartilage tissue engineering and repair.
The problem being addressed is the relatively weak biological activity of naturally occurring triterpenoids and the need for potent compounds that can effectively induce stem/progenitor cell differentiation to treat degenerative and congenital bone and cartilage diseases. Existing synthetic analogs of oleanolic acid, such as CDDO derivatives, had been developed for anti-inflammatory and anti-carcinogenic purposes but their application to stem cell differentiation and tissue repair had not been exploited prior to this invention.
Claims Coverage
This patent contains two main independent claims focused on methods of producing stem or progenitor cells with induced gene expression using synthetic triterpenoids, and methods where the cell is multipotent.
Method for inducing gene expression in stem or progenitor cells using synthetic triterpenoids
A method comprises contacting a stem or progenitor cell ex vivo with an effective amount of a synthetic triterpenoid to induce expression of one or more specific genes: SOX9, COL2A1, TGF-β1, TGF-β2, TGF-β3, BMP2, BMP4, BMPRII, SMAD3, SMAD4, SMAD6, SMAD7, TIMP-1, or TIMP-2 in the cell.
Using specified types of stem or progenitor cells in the method
The stem or progenitor cell is selected from mesenchymal stem cells, adipose tissue-derived mesenchymal stem cells, embryonic stem cells, stem cells from exfoliated deciduous teeth, periosteum cells, osteoprogenitor cells, or growth plate progenitor cells.
Use of a synthetic triterpenoid compound of defined chemical structure
The synthetic triterpenoid has a defined chemical structure per Formula I, encompassing substituted synthetic oleanane triterpenoids including specific compounds such as CDDO, CDDO-Me, CDDO-MA, CDDO-TFEA, CDDO-EA, and CDDO-Im.
Method variants specifying multipotent stem or progenitor cells
The method includes embodiments where the stem or progenitor cell is multipotent.
The claims cover methods for inducing gene expression associated with differentiation in selected stem or progenitor cells by contacting them ex vivo with defined synthetic triterpenoids, including specific chemical compounds, and specify that the cells can be multipotent. This patent provides foundational methods for manipulating stem/progenitor cell gene expression and differentiation using these synthetic compounds.
Stated Advantages
Synthetic triterpenoids provide a potent means to induce gene expression and differentiation in stem or progenitor cells relevant for bone and cartilage regeneration.
The induced expression of specific genes such as SOX9 and BMPs allows for the directed differentiation of stem cells into chondrocyte-like or osteoblastic lineages, useful for treating degenerative and congenital skeletal conditions.
The methods enable therapeutic cell preparations for transplantation to treat injuries and diseases like osteoarthritis, rheumatoid arthritis, degenerative disc disease, bone injuries, cartilage repair, and skeletal disorders such as dwarfism and scoliosis.
Documented Applications
Treatment of degenerative diseases or conditions including bone injury, cartilage injury, joint injury, dental disease, osteoarthritis, rheumatoid arthritis, degenerative disc disease, kyphosis, and osteopenia.
Treatment of congenital disorders such as scoliosis and skeletal disorders including dwarfism.
Use of synthetic triterpenoid-treated stem or progenitor cells for tissue engineering and transplantation therapies for cartilage defects, periodontal bone grafts, and spinal fusion.
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