Hyaluronic acid binding domain-growth factor fusion protein cDNAs and fusion proteins for cartilage matrix preservation and repair
Inventors
Trippel, Stephen B. • Shi, Shuiliang
Assignees
US Department of Veterans Affairs • Indiana University Bloomington
Publication Number
US-10434188-B1
Publication Date
2019-10-08
Expiration Date
2034-06-03
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Abstract
The present invention provides fusion proteins including a hyaluronic acid-binding domain of a cartilage matrix protein and a conserved region of a growth factor protein. Certain embodiments provide nucleic nucleic acid sequences encoding a fusion protein and compositions thereof. Methods for using fusion polypeptides and nucleic acid molecules discloses herein are also provided. In certain embodiments, the fusion proteins and/or nucleic acid molecules can be used to treat a cartilage matrix protein-related condition in a subject.
Core Innovation
The invention provides fusion proteins comprising a hyaluronic acid-binding (HAB) domain derived from cartilage matrix proteins and a conserved region of a growth factor (GF) protein. These fusion proteins are encoded by isolated nucleic acid molecules and can optionally include signal peptides, linker sequences, protease cleavage sites, and additional functional peptides. The fusion proteins are designed to upregulate glycosaminoglycan (GAG) expression in chondrocytes and have enhanced retention in articular cartilage by binding to hyaluronic acid, facilitating improved cartilage matrix preservation and repair.
The invention addresses the clinical problem that articular cartilage damage, a major cause of arthritis and joint trauma, lacks effective self-repair capabilities. Current growth factor therapies, such as insulin-like growth factor-I (IGF-1), are limited by rapid elimination from the joint, slow diffusion into cartilage, and limited chondrocyte responsiveness. The fusion protein concept overcomes these limitations by combining a hyaluronic acid-binding domain for matrix retention with a growth factor for promoting chondrocyte reparative activity, thereby enabling sustained local delivery and enhanced biological effects.
Claims Coverage
The patent includes one independent fusion protein claim and one independent nucleic acid claim, each expressing inventive features related to the structure and function of the fusion proteins and their coding sequences. The claims cover various molecular components, arrangements, and uses of the fusion proteins.
Fusion protein comprising a specific HAB polypeptide linked to a conserved growth factor region
The fusion protein comprises a hyaluronic acid-binding polypeptide containing amino acids 1-178 of SEQ ID NO: 72 linked to a conserved region of a growth factor (GF) protein. The fusion protein is capable of upregulating glycosaminoglycan (GAG) expression in chondrocytes.
Inclusion of auxiliary molecular elements enhancing fusion protein functionality
The fusion protein may further include one or more elements selected from a signal peptide (SP), linker peptide, protease cleavage site, and an E peptide. The signal peptide can be selected from aggrecan, CD44, link protein, TSG-6, or versican signal peptides, and linkers include sequences such as SEQ ID NOS 1-8. Protease cleavage sites can be chosen from SEQ ID NOS 9-13.
Encoding nucleic acid molecules comprising sequences for fusion protein and auxiliary elements
Nucleic acid molecules encode the fusion protein and may include sequences encoding signal peptides, linker sequences, protease cleavage sites, E peptides, and additional functional peptides. These sequences are operably linked to express functional fusion proteins, and nucleic acids may be DNA or RNA.
Variants comprising flanking amino acids at N- or C-terminus of the HAB polypeptide
The fusion protein and encoding nucleic acid can comprise flanking amino acids to the HAB polypeptide at the N-terminus or C-terminus, in quantities selected from a defined range including 5 to 60 amino acids.
Expression vectors and transformed cells producing the fusion protein
Expression vectors encoding the fusion protein include plasmids and viruses such as adeno-associated virus (pAAV), enabling transformation, transfection, or transduction of host cells, including chondrocytes, to produce the fusion protein.
Methods of upregulating GAG expression and treating cartilage-related conditions
Methods include expressing the nucleic acid molecule or administering the fusion protein to chondrocytes to upregulate GAG expression and treating cartilage matrix protein-related conditions such as joint stiffness, degenerative disease, osteoarthritis, rheumatoid arthritis, and others by administering the fusion protein intra-articularly or to target tissues.
The claims collectively cover fusion proteins combining a specified HAB domain with a growth factor region capable of stimulating chondrocyte GAG production, nucleic acid sequences encoding these proteins with various auxiliary elements and configurations, vectors and cells producing these proteins, and methods of using these fusion proteins or nucleic acids for cartilage repair and treatment of related pathologies.
Stated Advantages
The fusion proteins provide retention within the articular cartilage matrix via hyaluronic acid binding, enabling sustained local delivery of growth factor.
Fusion proteins stimulate chondrocyte reparative activity, including upregulation of glycosaminoglycan production, promoting cartilage biosynthesis and repair.
The inclusion of protease cleavage sites allows regulated release of growth factors from the matrix, enhancing therapeutic control.
Fusion proteins overcome limitations of native growth factor therapies by reducing rapid joint clearance and increasing target tissue diffusion.
Documented Applications
Treatment of cartilage matrix protein-related conditions such as joint stiffness, degenerative diseases, facet disease, osteoarthritis, and rheumatoid arthritis.
Amelioration of joint pain or intervertebral disc pain in subjects.
Amelioration of symptoms resulting from joint or intervertebral disc injury, including traumatic injury, surgical injury, degenerative disease, developmental defects, and work injury.
Increasing sports performance in athletes by administration to joints or intervertebral discs.
Use in various mammalian subjects including laboratory animals, companion animals, draft animals, meat animals, and humans, and in cartilage from various anatomical sites including toe, ankle, knee, hip, spine, shoulder, neck, elbow, wrist, fingers, thumb, nose, ear, and intervertebral discs.
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