Self-assembling peptide amphiphiles displaying a transforming growth factor beta 1 (TGF-ß1) mimetic epitope
Inventors
YUAN, Shelby Chi • Stupp, Samuel I. • Sather, Nicholas A.
Assignees
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Publication Number
US-12570709-B2
Publication Date
2026-03-10
Expiration Date
Abstract
Provided herein are self-assembling peptide amphiphiles (PAs) comprising a bioactive Transforming growth factor beta 1 (TGF-β1) mimetic epitope, high-aspect-ratio nanostructures of PAs displaying a TGF-β1 mimetic epitope, and methods of enhancing cartilage regeneration/repair and/or treatment of osteoarthritis and other musculoskeletal injuries and diseases.
Core Innovation
The invention relates to bioactive peptide amphiphiles (PAs) that present a TGF-β1 mimetic epitope peptide comprising CESPLKRQC (SEQ ID NO: 1) on self-assembling, high-aspect-ratio PA nanostructures. The PA composition includes a hydrophobic non-peptidic segment, a β-sheet-forming peptide segment, and an acidic peptide segment, and the TGF-β1 mimetic epitope peptide is cyclized via disulfide bonds between terminal cysteine residues.
The disclosed concept couples epitope cyclization with surface presentation on PA nanostructures to produce long fibrous morphologies. The surface presentation is associated with enhanced chondrocyte signaling through TGF-β pathway activation, including p-Smad2 activation and sustained chondrocyte phenotype in three-dimensional gels.
As documented in the partial content, the approach is used for cartilage regeneration/repair and for treating osteoarthritis or musculoskeletal injury, including improved in vivo retention/integration using a PA/hyaluronic-acid slurry in a rabbit osteochondral defect model.
Claims Coverage
The independent claim clm-00001 is directed to a specific bioactive peptide amphiphile composition architecture with four components and a cyclic TGF-β1 mimetic epitope. Across the claim set referenced in the partial content, the inventive features refine the β-sheet-forming segment and the backbone diluent PA options, optionally constrain bioactive-to-diluent mol%, and extend to administration for cartilage repair/regeneration and osteoarthritis or musculoskeletal disease/injury treatment or prevention.
Cyclic TGF-β1 mimetic epitope peptide on a bioactive PA composition
A composition comprising a bioactive peptide amphiphile (PA) comprising a hydrophobic non-peptidic segment, a β-sheet-forming peptide segment, an acidic peptide segment, and a TGF-β1 mimetic epitope peptide, wherein the TGF-β1 mimetic epitope peptide consists of CESPLKRQC (SEQ ID NO: 1), and wherein the TGF-β1 mimetic epitope peptide is cyclized via disulfide bonds between the terminal cysteine residues.
Defined β-sheet-forming peptide segment options for the bioactive PA
Selecting the β-sheet-forming peptide segment from VVVAAA (SEQ ID NO: 3), AAAVVV (SEQ ID NO: 4), AAVV (SEQ ID NO: 5), VVAA (SEQ ID NO: 6), AA, VV, VA, and AV.
Specific backbone PA diluent peptide amphiphile variants
A backbone PA diluent peptide amphiphile selected from C16-AAEE (SEQ ID NO: 7), C16-AEAE (SEQ ID NO: 8), or C16-VVVAAAEEE (SEQ ID NO: 9).
Bioactive and diluent peptide amphiphile co-assembly ratio constraint
The composition is defined such that 5% to 95% (by mol) bioactive peptide amphiphile and 5% to 95% (by mol) diluent peptide amphiphile are present.
Helical ribbon-like co-assembled structure with size constraint
The bioactive PA and the diluent PA co-assemble into a helical ribbon-like structure with an average diameter of 50 to 60 nm.
Administration to promote cartilage repair/regeneration and treat or prevent osteoarthritis or musculoskeletal disease/injury
Administering the composition to a subject to promote cartilage repair or regeneration and to treat or prevent osteoarthritis or a musculoskeletal disease or injury when the subject has a cartilage defect or injury or is at elevated risk.
Overall, the claim coverage centers on a bioactive PA composition architecture with a cyclized CESPLKRQC (SEQ ID NO: 1) TGF-β1 mimetic epitope presented via a hydrophobic segment, a β-sheet-forming segment, and an acidic segment; refinements in the partial content include specific β-sheet-forming segment options, specified diluent backbone PA variants, optional quantitative bioactive/diluent mol% constraints, and a helical ribbon-like co-assembly morphology with a defined average diameter, as well as a medical-use administration context for cartilage repair/regeneration and osteoarthritis or musculoskeletal disease/injury treatment or prevention.
Stated Advantages
Enhanced chondrocyte signaling through TGF-β pathway activation, including p-Smad2 activation.
Upregulation of extracellular matrix proteins including collagen II, COMP, and aggrecan.
Sustained chondrocyte phenotype in three-dimensional gels.
Long fibrous morphologies associated with cyclization and surface presentation on PA nanostructures.
Improved in vivo retention/integration using a PA/hyaluronic-acid slurry in a rabbit osteochondral defect model.
Documented Applications
Promoting cartilage repair or regeneration in the context of a cartilage defect or injury.
Treating or preventing osteoarthritis in a subject having a cartilage defect or injury or at elevated risk.
Treating or preventing a musculoskeletal disease or injury in a subject having a cartilage defect or injury or at elevated risk.
Using a PA/hyaluronic-acid slurry in a rabbit osteochondral defect model to improve in vivo retention/integration.
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